Coffee and Health: A Review of Recent Human Research

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JANE V. HIGDON and BALZ FREI

Critical Reviews in Food Science and Nutrition, 46:101–123 (2006)
Copyright C__ Taylor and Francis Group, LLC
ISSN: 1040-8398
DOI: 10.1080/10408390500400009

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331

Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterolraising effects of coffee. The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson’s disease and liver disease (cirrhosis and hepatocellular carcinoma). Most prospective cohort studies have not found coffee consumption to be associated with significantly increased cardiovascular disease risk. However, coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure and plasma homocysteine. At present, there is little evidence that coffee consumption increases the risk of cancer. For adults consuming moderate amounts of coffee (3–4 cups/d providing 300–400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. However, some groups, including people with hypertension, children, adolescents, and the elderly, may be more vulnerable to the adverse effects of caffeine.
In addition, currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.

Keywords: caffeine, type 2 diabetes, Parkinson’s disease, liver disease, cardiovascular disease, pregnancy


INTRODUCTION

Coffee, an infusion of ground, roasted coffee beans, is reported to be among the most widely consumed beverages in the world. Although coffee is lauded for its aroma and flavor, its caffeine content likely plays a role in its popularity. In fact, coffee is a complex chemical mixture reported to contain more than a thousand different chemicals, including carbohydrates, lipids, nitrogenous compounds, vitamins, minerals, alkaloids and phenolic compounds.1 The majority of studies on the health effects of coffee consumption in humans are observational. Concerns about potential health risks of coffee and caffeine consumption raised by epidemiological research in the past were likely exacerbated by associations between high intakes of coffee and unhealthy behaviors, such as cigarette smoking and physical inactivity.2 More recently, coffee consumption has been associated with reductions in the risk of several chronic diseases.3–5 However, in many cases, conflicting findings and concerns about methodological issues have made it difficult for health professionals and the public to interpret the available evidence on coffee consumption and health. The purpose of this article is to review and interpret relatively recent research on the benefits and risks of coffee consumption in humans.

Address correspondence to Jane Higdon, Ph.D., Linus Pauling Institute,
Oregon State University, Corvallis, OR 97331. E-mail: jane.higdon@
oregonstate.edu

COMPOUNDS IN COFFEE THAT MAY AFFECT HUMAN HEALTH
Caffeine

Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid that occurs naturally in coffee beans (Figure 1).1 At intake levels associated with coffee consumption, caffeine appears to exert most of its biological effects through the antagonism of the A1 and A2A subtypes of the adenosine receptor.6 Adenosine (Figure 1) is an endogenous neuromodulator with mostly inhibitory effects, and adenosine antagonism by caffeine results in effects that are generally stimulatory. Some physiological effects associated with caffeine administration include central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, and diuresis.7 Caffeine is rapidly and almost completely absorbed in the stomach and small intestine and distributed to all tissues, including the brain. Caffeine metabolism occurs primarily in the liver, where the activity of the cytochrome

Figure 1 Chemical structures of caffeine and adenosine.

P450 isoform CYP1A2 accounts for almost 95% of the primary metabolism of caffeine. CYP1A2-catalyzed 3-demethylation of caffeine results in the formation of 1,7-dimethylxanthine (paraxanthine) (Figure 2). Paraxanthine may be demethylated by CYP1A2 to form 1-methylxanthine, which may be oxidized to 1-methyluric acid by xanthine oxidase. Paraxanthine may also be hydroxylated by CYP2A6 to form 1,7-dimethyluric acid, or acetylated by N-acetyltransferase 2 (NAT2) to form 5-acetylamino-6-formylamino-3-methyluracil, an unstable compound that may be deformylated nonenzymatically to form 5-acetylamino-6-amino-3-methyluracil (Figure 2).8,9 Caffeine concentrations in coffee beverages can be quite variable.
A standard cup of coffee is often assumed to provide 100 mg of caffeine, but a recent analysis of 14 different specialty coffees purchased at coffee shops in the US found that the amount of caffeine in 8 oz (?240 ml) of brewed coffee ranged from 72–130 mg.10 Caffeine in espresso coffees ranged from 58–76 mg in a single shot. Interestingly, the caffeine content of the same type of coffee purchased from the same store on six separate days varied from 130 to 282 mg per 8-oz serving.

Cafestol and Kahweol
Coffee consumption has been associated with higher serum total and LDL cholesterol concentrations in some observational studies but not others.11 The observation that the positive association between coffee consumption and serum cholesterol was more consistent in Scandinavia, where boiled coffee was popular at the time, than in other European countries and the US, where filtered coffee was more popular, led to the hypothesis that the brewing method was critical to the cholesterol-raising effect of coffee.12 A meta-analysis of 14 randomized controlledtrials examining the effect of coffee consumption on serum cholesterol concentrations found that the consumption of boiled coffee dose-dependently increased serum total and LDL
cholesterol concentrations, while the consumption of filtered coffee resulted in very little increase in serum cholesterol.13
The cholesterol-raising factors, first isolated in coffee oil, were later found to be the diterpenes, cafestol and kahweol (Figure 3).12 These diterpenes are extracted from ground coffee during brewing, but are mostly removed from coffee by paper filters. Scandinavian boiled coffee, Turkish coffee, and French press (cafetiere) coffee contain relatively high levels of cafestol and kahweol (6–12 mg/cup), while filtered coffee, percolated coffee, and instant coffee contain low levels of cafestol and kahweol (0.2–0.6 mg/cup).14,15 Although diterpene concentrations are relatively high in espresso coffee, the small serving size makes it an intermediate source of cafestol and kahweol (4 mg/cup). Studies in ileostomy patients indicate that about
70% of the cafestol and kahweol in unfiltered coffee is absorbed intestinally.16 The mechanisms for the effects of these diterpenes on lipoprotein metabolism are not yet clear, but consumption of cafestol and kahweol in French press coffee has been found to result in persistent increases in cholesterol ester transfer protein
(CETP) activity in humans, which may contribute to increases in LDL cholesterol.17 CETP transfers cholesteryl esters from HDL to the apolipoprotein B-containing lipoproteins, LDL and VLDL.

Chlorogenic Acid
Chlorogenic acids are a family of esters formed between quinic and trans-cinnamic acids, which are an important group of dietary phenols (Figure 4).18 The most common individual chlorogenic acid is 5-O-caffeoylquinic acid, which is still often called chlorogenic acid. For those who drink it, coffee represents the richest dietary source of chlorogenic acids and cinnamic acids (caffeic acid). The chlorogenic acid content of a 200 ml (7-oz) cup of coffee has been reported to range from 70–350 mg, whichwould provide about 35–175 mg of caffeic acid.18 Studies in colostomy patients indicate that about33%of ingested chlorogenic acid and 95% of caffeic acid are absorbed intestinally.192; XO, xanthine oxidase.

Figure 2 Major pathways in caffeine metabolism. Abbreviations: CYP1A2, cytochrome P450 1A2; CYP2A6, cytochrome P450 2A6;NAT2, N-acetyl transferase

Figure 3 Chemical structures of cafestol and kahweol, diterpenes in coffee with cholesterol-raising effects. R= H: free diterpene; R= fatty acid: diterpene ester.

Thus, about two–thirds of ingested chlorogenic acid reaches the colon where it may be metabolized by the colonic microflora.20
In the colon, chlorogenic acid is likely hydrolyzed to caffeic acid and quinic acid. The presence of bacterial metabolites of chlorogenic acid in the urine suggests that they are absorbed in the colon. Although chlorogenic acid and caffeic acid have antioxidant activity in vitro,21 it is unclear how much antioxidant
activity they contribute in vivo because they are extensively metabolized, and the metabolites often have lower antioxidant activity than the parent compounds.

Figure 4 Chemical structure of 5-O-cafeoylquinic acid (chlorogenic acid).

Micronutrients
Several micronutrients found in coffee, including magnesium, potassium, niacin, and vitamin E, could contribute to the observed health effects of coffee consumption. According to theUSDA Nutrient database, 8 oz (?240 ml) of brewed coffee provide 7mg of magnesium and 1 oz (?30 ml) of espresso provides
24 mg of magnesium.22 Thus, one cup of coffee could contribute 1–5% of the recommended dietary allowance (RDA) for magnesium (420 mg/d) in adult men.23 An 8-oz cup of brewed coffee is reported to provide 116 mg of potassium and a 1-oz shot of espresso 34 mg,22 suggesting that one cup of coffee contributes only 1–2% of the adequate intake (AI) for potassium (4700 mg/d) in adults.24 Trigenolline in coffee beans is demethylated to form nicotinic acid during the roasting process.25 Coffee has been reported to provide 1–3 mg of nicotinic acid per cup.25 Thus, one cup of coffee could contribute 6–18% of the RDA for niacin (16 mg/d) in adult men.26 Coffee does not appear to be an important source of dietary vitamin E since one cup provides about 0.2 mg of ?-tocopherol and 0.2 mg of ? -tocopherol,22 about 0.1% of the adult RDA for vitamin E (15 mg/d of RRR- ?-tocopherol).27


METHODOLOGICAL ISSUES IN EPIDEMIOLOGICAL RESEARCH ON COFFEE

Much of the currently available information on the health effects of coffee is derived from epidemiological research. However, the study of coffee consumption in human populations raises several issues regarding exposure classification and potential confounders that should be considered when interpreting the results of epidemiological studies of coffee consumption.

Exposure Misclassification
Coffee exposure is often assessed using food frequency questionnaires that collect information regarding the number of cups of coffee consumed daily or weekly.However, cup size may vary considerably depending on the population. One study in the US found that cup sizes used by pregnant women ranged from 2–32 oz, with 7-8-oz cups accounting for only30%of cup sizes used.28
In epidemiological studies, one cup of coffee is often assumed to provide 85–100 mg of caffeine. However, the caffeine content of different coffees can vary considerably (see above), and it is possible that people who drink many cups of coffee on a daily basis consume weaker coffee than people who drink only 1–2 cups daily. Until recently, few epidemiological studies collected information about the brewing process used to prepare coffee.
This information became important when it was discovered that cholesterol-raising compounds in coffee were largely removed by paper filters (see above).12 Finally, individual variation in the metabolism of compounds in coffee may increase or decrease the exposure of an individual to a bioactive compound in coffee.
For example, NAT2 plays an important role in the metabolism of caffeine.7 A genetic polymorphism in the NAT2 gene, which results in “fast acetylators” and “slow acetylators,” is likely to affect individual exposure to caffeine metabolites (see Considerations for Future Research below). Additionally, cigarette smoking increases caffeine clearance by inducing CYP1A2 activity,29 and smokers have been found to have lower plasma levels of caffeine than nonsmokers at the same level of consumption.30
It is not yet known how genetic and lifestyle factors affect individual exposure to other bioactive compounds in coffee

Confounders
A frequent criticism of epidemiological research on coffee is inadequate adjustment for confounding factors that could influence the relationship between coffee consumption and health outcomes. Cigarette smoking is often cited as a potential confounder because high intakes of coffee are frequently associated with cigarette smoking.31 Most analyses are adjusted for the effect of cigarette smoking. However, underreporting of a socially undesirable behavior, such as smoking, while accurately reporting a socially neutral behavior, such as coffee consumption, could lead to inadequate adjustment for the effect of smoking and overestimation of the effect of coffee consumption on a health outcome. This concern may be particularly relevant to studies of pregnant women. Other lifestyle factors may also confound associations between coffee consumption and health outcomes. For example, people who drink coffee in Scotland tend to be younger, have higher incomes, and are generally healthier than people who drink tea.32 This may not be the case in other countries. Health outcomes in consumers of regular coffee are sometimes compared to those in consumers of decaffeinated coffee in order to determine whether a health effect is related to caffeine or other compounds in coffee. However, a study of the traits of decaffeinated coffee consumers in the US found that decaffeinated coffee use was related to a history of illness in some people but to a healthy lifestyle in other people.33 When evaluating health outcomes in decaffeinated coffee users, most epidemiological studies do not distinguish between former users of caffeinated coffee, who may have switched to decaffeinated coffee because of a health problem, and never users who may be avoiding caffeine as part of a healthy lifestyle.

POTENTIAL HEALTH BENEFITS OF COFFEECONSUMPTION
Prevention of Type 2 Diabetes Mellitus
Epidemiological Studies

Six out of nine prospective cohort studies have found a significant inverse association between the risk of type 2 diabetes mellitus (DM) and coffee intake (Table 1).5,34–37 A prospective study of more than 17,000 Dutch men and women found that the risk of developing type 2 DM was 50% lower in those who consumed at least 7 cups of coffee daily compared to those who drank 2 cups or less.37 In Finland, where coffee consumption is among the highest in the world, a study that followed more than 14,000 men and women for an average of 12 years found that men who drank at least 10 cups of coffee daily had a 55% lower risk of developing type 2DMthan men who drank 2 cups or less, while women who drank at least 10 cups daily had a risk of type
2 DM that was 79% lower.36 In a cohort of more than 10,000 Finnish twins, those who consumed at least 7 cups of coffee daily had a 35% lower risk of type 2 DM than those who consumed 2 cups or less.34 In a smaller cohort of Swedish women followed for 18 years, those who drank at least 3 cups of coffee daily had a risk of type 2 DMthat was about 50% lower than the risk for those who consumed less than 2 cups daily.35 The two largest prospective cohort studies to examine the relationship between coffee consumption and type 2 DM were the Health Professionals Follow-up Study (41,934 men) and the Nurses’ Health Study (84,276 women) in the US.5 Men who drank at least 6 cups of coffee daily had a 54% lower risk of developing type 2 DM than men who did not drink coffee, and women who drank at least 6 cups of coffee daily had a 29% lower risk than women who did not drink coffee. In both cohorts, higher caffeine intakes were also associated with significant risk reductions. A more modest inverse association between decaffeinated coffee consumption and the risk of type 2 DM was also observed in both men and women, suggesting that compounds other than caffeine may have protective effects. In contrast, tea consumption was not associated with type 2 DM risk in the Dutch37 or American cohorts.5

Not all prospective cohort studies have observed significant inverse associations between coffee consumption and type 2DM risk. In an earlier Finnish study that enrolled more than 19,000 men and women between 1973 and 1977, consumption of as much as 7 cups of coffee daily was not associated with the risk of type 2DMafter an average of 14 years of follow-up.38 The investigators hypothesized that the difference in findings between the two Finnish cohorts35,37 may have been due to the fact that boiled coffeewas more commonly consumed than filtered coffee at the start of the earlier study. Although the later Finnish study found that consumption of either boiled coffee or filtered coffee was associated with a significant reduction in type 2 DM risk, men who consumed boiled coffee were almost three times as likely to report developing type 2 DM than men who consumed filtered coffee.36 Prospective studies in two smaller cohorts did not observe significant associations between coffee consumption and type 2 DM diagnosed by oral glucose tolerance testing (OGTT) instead of self-report.39,40 In a Dutch cohort, coffee consumption as high as 7 cups/d was not associated with a statistically significant reduction in the risk of type 2 DM after 6 years of follow-up, but a significant inverse association between coffee consumption and the risk of impaired glucose tolerance was observed.40 A prospective study of Pima Indians in theUSfound no association between coffee consumption and the risk of type 2 DM, despite the large number of cases that developed in this high-risk cohort over the 11-year follow-up period.39
It should be noted that coffee consumption among the PimaIndians was relatively low compared to coffee consumption in cohorts where significant inverse associations were observed. Recently, a systematic review of nine prospective cohort studies, including more than 193,000 men andwomen, found that the risk of type 2DMwas 35% lower in those who consumed at least 6 cups of coffee daily and 28% lower in those who consumed between 4–6 cups/d compared to those who consumed less than 2 cups/d.41

Glucose Tolerance and Insulin Sensitivity

Acute caffeine administration has been found to impair glucose tolerance and to decrease insulin sensitivity in a number of controlled clinical trials.42–45 Several randomized controlled trials have examined the effect of coffee consumption for 2–4 weeks on serum glucose and insulin levels. When healthy volunteers who usually consumed an average of 560 mg/d of caffeine from coffee or tea consumed only decaffeinated coffee for 14 days, average fasting blood glucose levels decreased significantly.46 Interestingly, substituting caffeinated coffee providing 850 mg/d for 20 days did not significantly increase fasting blood glucose compared to decaffeinated coffee. More recently, the effects of coffee consumption on serum glucose and insulin levels were examined in two studies originally designed to assess the effect of coffee consumption on plasma homocysteine concentrations.47 In one trial, participants who normally consumed 5–8 cups/d of coffee were assigned in random order to a 4-week period in which they consumed one liter of filtered coffee daily providing 1100 mg/d of caffeine and a 4-week period in which they consumed no coffee. Although fasting glucose levels did not differ between the two treatment periods, serum insulin levels increased during the period that coffee was consumed, suggesting decreased insulin sensitivity.
In a separate crossover trial, participants who normally consumed more than 6 cups of coffee daily consumed 870 mg/d of caffeine, 900 ml/d of coffee providing 870 mg/d of caffeine, and a placebo for 2 weeks each in a randomly assigned order.47
Serum insulin levels were nonsignificantly increased during the coffee period compared to placebo, but fasting glucose levels did not differ among the three groups.

Although acute and short-term trials of caffeine and coffee consumption have not demonstrated improvements in glucose tolerance or insulin sensitivity, the results of several epidemiological studies suggest that long-term, habitual coffee consumption may help maintain normal glucose tolerance. Several cross-sectional studies in Japan,48 Spain,49 and Sweden50 have found coffee intake to be inversely associated with the incidence of impaired glucose tolerance after an oral glucose load. Additionally, a prospective cohort study of more than 1100 Dutch men and women found that coffee intake was inversely associated with the risk of developing impaired glucose tolerance over the next 6 years.40 Those who drank at least 5 cups of coffee daily had a risk of developing impaired glucose tolerance that was 50% lower than those who drank 2 cups/d or less. Coffee intake was not associated with the risk of impaired fasting glucose, suggesting that habitual coffee consumption affects post-load rather than fasting glucose metabolism.

Potential Mechanisms for Inverse Associations between Coffee and Type 2 Diabetes Mellitus
Inhibition of the Glucose-6-Phosphatase System by Chlorogenic Acid. The hydrolysis of glucose-6-phosphate to glucose and phosphate represents the terminal step of the glucoseproducing pathways, gluconeogenesis and glycogenolysis.51
Glucose-6-phosphate hydrolysis requires the coupled function of glucose-6-phosphatase, a glucose-6-phosphate translocase protein, and a second translocase protein. Chlorogenic acid has been shown to be a specific competitive inhibitor of the glucose- 6-phosphate translocase in rat liver microsomes.52

Inhibition of Intestinal Glucose Absorption by Chlorogenic Acid or other Phenolic Compounds in Coffee.
Chlorogenic acid reduced sodium-dependent glucose transport in brush border membrane vesicles isolated from rat small intestine.53 Glucosedependent insulinotropic polypeptide (GIP) and glucagon-like
peptide-1 (GLP-1) are intestinal hormones that augment insulin secretion after oral glucose consumption. Consumption of decaffeinated coffee with an oral glucose load decreased plasma concentrations of GIP, which is secreted in the proximal small intestine, and increased plasma concentrations of GLP-1, which is secreted in the distal small intestine, suggesting that compounds in coffee may slow intestinal glucose absorption.54

Increased Magnesium Intake. Dietary magnesium intake and serum magnesium concentrations have been inversely associated with the risk of type 2 DM in several large prospective cohort studies.55–57 Additionally, several short-term clinical trials have found that magnesium supplementation improves insulin sensitivity in individuals with low serum or erythrocyte magnesium concentrations.58–60 However, it is unclear whether coffee represents an important source of dietary magnesium (see above). In the Nurses’ Health Study and Health Professionals Follow-up Study cohorts, the statistically significant inverse association between coffee consumption and type 2 DM risk persisted after adjustment for dietary magnesium intake.5

Energy Expenditure and Weight Loss. Caffeine has been found to increase the resting metabolic rate in lean as well as obese individuals for up to 24 hours after ingestion.61–63 However, controlled trials have not generally found that caffeine alone is effective in promoting weight loss in overweight adults.64 Higher coffee consumption was actually associated with higher BMI values in several European cohorts,35–37 but coffee intake was not significantly associated with BMI in the Nurses’ Health Study or the Health Professionals Follow-up Study in the US.5 Recently, a prospective study that followed more than 7000 US adults for an average of 8 years found that the significant inverse association between coffee intake and the risk of type 2 DM observed in the entire cohort applied only to those people ?60 years of age who had previously lost
weight.65 Although the significance of this finding requires further clarification, it suggests that weight loss may play a role in the beneficial effect of coffee consumption on the risk of type2 DM.

Summary:
Coffee and Type 2 Diabetes Mellitus

Large prospective cohort studies in the Netherlands, US, Finland, and Sweden have found coffee consumption to be associated with significant dose-dependent reductions in the risk of developing type 2 DM. Although short-term clinical trials have found that caffeine administration impairs glucose tolerance and decreases insulin sensitivity, limited data from epidemiological studies suggest that habitual coffee consumption is inversely associated with impaired glucose tolerance. Until the relationship between long-term coffee consumption and type 2 DMrisk is better understood, it is premature to recommend coffee consumption as a means of preventing type 2 DM.5,41

Prevention of Parkinson’s Disease

Epidemiological Studies

Overall, the results of case-control studies suggest that coffee and caffeine intakes are inversely associated with the risk of Parkinson’s disease.66 Several large prospective cohort studies have also found inverse associations between coffee and caffeine intakes and Parkinson’s disease risk in men (Table 2). A study
of more than 8,000 Japanese-American men found that thosemwho did not drink coffee were 3–5 times more likely to develop Parkinson’s disease over the next 24–30 years than those who drank at least 28 oz daily.67 Caffeine intakes from coffee and other sources were also inversely associated with Parkinson’s disease risk. Similarly, in the Health Professionals Follow-up Study, men who regularly consumed at least one cup of coffee daily had a risk of developing Parkinson’s disease over the next 10 years that was about half that of men who did not drink coffee.3 The consumption of tea and other caffeinated beverages was also inversely associated with Parkinson’s disease risk. In contrast, inverse associations between coffee and caffeine consumption and Parkinson’s disease risk over a 16-year period were not observed in the Nurses’ Health Study.3 Similarly, in the Cancer Prevention Study (CPS) II cohort of more than 500,000 men and women in the US, coffee consumption was inversely associated with Parkinson’s disease mortality in men but not women.68 The failure of prospective studies to find an inverse relationship between coffee consumption and Parkinson’s disease in women may be due to the modifying effect of estrogen replacement therapy.69 Further analysis of the Nurses’ Health Study cohort revealed that coffee consumption was inversely associated with Parkinson’s disease risk in women who had never used postmenopausal estrogen, but a significant increase
in Parkinson’s disease risk was observed in postmenopausal estrogen users who drank at least 6 cups of coffee daily.70 In the CPS II cohort, a significant inverse association between coffee consumption and Parkinson’s disease mortality was also observed in women who had never used postmenopausal estrogen, but not in those who used postmenopausal estrogen.68 It is not clear how estrogen use modifies the effect of caffeine on Parkinson’s disease risk. However, caffeine is largely metabolized by hepatic CYP1A2, and the use of postmenopausal estrogen replacement therapy has been found to inhibit CYP1A2-mediated
caffeine metabolism.71


Potential Mechanisms for Inverse Associations between Caffeine and Parkinson’s Disease

Although the results of epidemiological studies suggest that caffeine consumption decreases the risk of Parkinson’s disease, other explanations for the inverse association between caffeine consumption and Parkinson’s disease risk have been proposed. For example, subtle changes in mood, sleep patterns, and the sense of smell, which have been proposed as symptoms of preclinical Parkinson’s disease, could lead to decreased caffeine consumption.69,72 However, this possibility seems unlikely since prospective cohort studies have observed strong inverse associations between Parkinson’s disease risk and caffeine consumption more than a decade before diagnosis. Another potential explanation is that a decreased propensity for addictive
behavior, e.g., cigarette smoking and caffeine consumption, has the same underlying cause as an increased risk of Parkinson’s disease.3 Recent research supports the idea that chronic caffeine consumption could reduce Parkinson’s disease risk. Parkinson’s disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra.73 Studies in animal models suggest that caffeine consumption decreases the risk of Parkinson’s disease by protecting against dopaminergic neurotoxicity.72 The effects of caffeine in the central nervous system are related to its activity as an antagonist of the A1 and A2A subtypes of the adenosine receptor.74 The expression of A2A-receptors in the brain is restricted almost entirely to the striatum, the target of the dopaminergic neurons that degenerate in Parkinson’s disease. Acute toxicity with 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) can induce Parkinsonism in humans.75 A well-established animal model of Parkinson’s disease uses MPTP to induce dopaminergic neurotoxicity in mice. Caffeine, at doses comparable to typical human exposures, has been found to attenuate MPTP-induced losses of striatal dopamine and dopamine transporter binding sites in mice.76 Specific A2A-receptor antagonists mimicked the effect of caffeine as did the absence of functional A2A-receptors in A2Areceptor knockout mice. At present, it is not known exactly how A2A-receptor blockade reduces dopaminergic neurotoxicity.77 Although the results of epidemiological and animal studies suggest that caffeine may reduce the risk of developing Parkinson’s
disease, it is premature to recommend increasing caffeine consumption to prevent Parkinson’s disease, particularly in women taking exogenous estrogens.

Suicide Risk

Two prospective cohort studies in the US found significant inverse associations between coffee consumption and the risk of suicide.78,79 A 10-year study of more than 128,000 men and women participating in a California health plan found that the relative risk of suicide decreased by 13% for every cup of coffee consumed daily. Similarly, a 10-year study of more than 86,000 women found that those who drank at least 2 cups of coffee daily had a risk of suicide that was 50% lower than those who did not drink coffee.78 Coffee consumption and suicide rates are higher in Finland than in the US. A prospective study that followed more than 43,000 Finnish men and women for an average of 14.6 years found that the relationship between coffee
consumption and suicide risk was J-shaped.80 Those who consumed at least 8 cups of coffee daily had a risk of suicide thatwas 58% higher than those with more moderate coffee consumption (0–7 cups/d). The reasons for the inverse association between moderate coffee consumption and the risk of suicide in these cohorts are not known. At present there is not enough evidence t support recommendations for coffee consumption in clinically depressed patients.

Prevention of Colorectal Cancer


Epidemiological Studies

In general, coffee consumption has been inversely associated with the risk of colon cancer in case-control studies, but not in prospective cohort studies.81,82 A meta-analysis that combined the results of 12 case-control studies and five prospective cohort studies found that people who drank 4 or more cups of coffee daily had a risk of colorectal cancer that was 24% lower than that of nondrinkers.82 However, coffee consumption was not associated with colorectal cancer risk when the results of only the prospective cohort studies were combined. Although case-control studies usually include more cancer cases than prospective cohort studies, they may be subject to recall bias with respect to coffee consumption and selection bias with respect to the control group. Similarly, a more recent review of epidemiological studies found evidence of an inverse association between coffee consumption and colon cancer risk from case-control studies but no evidence of such an association from prospective cohort studies.81 No overall associations between coffee and rectal cancer emerged in this review. In contrast, the two largest prospective cohort studies to examine the relationship between coffee and colorectal cancer to date found that American men and women who regularly consumed 2 or more cups of decaffeinated coffee daily had a risk of rectal cancer that was 48% lower than those who never consumed caffeinated coffee.83 Consumption of caffeinated coffee, tea, and caffeine were not associated with either colon or rectal cancer risk. Casecontrol studies have not generally found coffee consumption to be inversely associated with the risk of colorectal adenoma,84–86 and coffee consumption was not associated with the risk of recurrent colorectal adenomas over a 4-year period.87

Potential Mechanisms for Inverse Associations between Coffee and Colorectal Cancer

Several mechanisms have been proposed to explain the inverse association between coffee consumption and colorectal cancer risk observed in case-control studies. It has been suggested that compounds in coffee, such as diterpenes, could decrease the synthesis and secretion of bile acids, which may promote colon carcinogenesis.81 However, two human intervention trials do not support the idea that coffee consumption decreases bile acid synthesis or secretion. Daily consumption of one liter of unfiltered coffee for 2 weeks did not decrease fecal soluble bile acids,88 and the daily consumption of coffee oil containing 69 mg of cafestol for 5 weeks did not appear to decrease the activity of cholesterol 7?-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid synthesis.89 Coffee consumption may increase colonic motility, decreasing the exposure of colonic epithelial cells to potential carcinogens.90 However, infrequent bowel movements were not associated with increased risk of colorectal cancer or adenomas in the Nurses’ Health Study cohort.91,92 In animal studies, diterpenes found in unfiltered coffee have been reported to decrease the formation of DNA-adducts by several genotoxic carcinogens, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine found in cooked meat and implicated in colon
carcinogenesis.93,94 Diterpenes in coffee may promote the elimination of carcinogens and improve antioxidant status by enhancing phase II enzyme activity and glutathione synthesis.95,96 Although, consumption of one liter of unfiltered coffee daily for 2 weeks did not increase colorectal glutathione-S-transferase activity in human volunteers, glutathione concentrations significantly increased in colorectal mucosa and plasma by 8% and 15%, respectively.88 Despite promising findings in case-control and animal studies, it is unclear whether coffee consumption decreases colon or rectal cancer risk in humans.

Hepatic Injury, Cirrhosis, and Hepatocellular Carcinoma
Liver injury resulting from chronic inflammation may result in cirrhosis. In cirrhosis, the formation of fibrotic scar tissue results in progressive deterioration of liver function and other complications, including hepatocellular carcinoma.97 The most common causes of cirrhosis in developed countries are alcohol abuse and viral hepatitis B and C infection.

Coffee and Hepatic Injury
Serum ? -glutamyl transferase (GGT) activity has been widely used as an index of hepatic injury and a marker of alcohol intake.98 A number of cross-sectional studies have found coffee consumption to be inversely associated with serum GGT activity.99–106 Elevated serum alanine aminotransferase (ALT) activity is a more specific marker of hepatic injury than GGT. An inverse association between coffee consumption and serum ALT activity has been observed in several cross-sectional studies.106–108 Recently, a large cross-sectional study in the US found that coffee and caffeine consumption were inversely associated with the risk of having an abnormally elevated serum ALT level (>43 U/L) in almost 6000 adults at high risk of hepatic injury from many different causes, including excessive alcohol consumption, viral hepatitis, iron overload, overweight, or impaired glucose metabolism.108 Liver damage and cirrhosis have been found to inhibit caffeine metabolism, raising the possibility that people with liver disease consume less coffee because they are more likely to experience adverse effects from caffeine.109,110 However, in at least one study, the inverse relationship between coffee consumption and serum ALT did not change when the analysis was limited to those without impaired liver function.108 The potential for liver disease to impair caffeine clearance highlights the importance of distinguishing between former coffee drinkers and nondrinkers in future epidemiological studies.

Coffee and Cirrhosis

Coffee consumption was inversely associated with the risk of cirrhosis in several case-control studies.111–113 and with mortality from alcoholic cirrhosis in two prospective cohortstudies.114,115 An 8-year study of more than 120,000 US men and women found that the risk of death from alcoholic cirrhosis was 22% lower per cup of coffee consumed daily.79 A 17-year study of more than 51,000 men and women in Norway found that those who consumed at least 2 cups of coffee daily had a 40% lower risk of death from cirrhosis than those who never consumed coffee.115

Coffee and Hepatocellular Carcinoma

Several case-control studies in Europe116,117 and at least two prospective cohort studies in Japan118,119 have observed significant inverse associations between coffee consumption and the risk of hepatocellular carcinoma. A prospective cohort study that followed more than 90,000 Japanese men and women for 10 years found that the risk of hepatocellular carcinoma decreased dose-dependently with increasing coffee consumption.118 Those who consumed at least 5 cups daily had a 76% lower risk of hepatocellular carcinoma than those who never drank coffee. In this study, the strongest inverse association was observed in people infected with the hepatitis C virus. Coffee consumption was not significantly associated with hepatocellular carcinoma risk in people who were not infected with hepatitis B or hepatitis C virus. A pooled analysis of two other prospective cohort studies in Japan that followed more than 50,000 men and women for 7–9 years found no significant association between coffee consumption and the risk of hepatocellular carcinoma in people who did not report a history of liver disease when the study began.119 However, in people with a history of liver disease at baseline, those who consumed at least one cup of coffee daily had a risk of hepatocellular carcinoma that was 48% lower than the risk for those who did not drink coffee.
Potential Mechanisms for Inverse Associations between Coffee and Hepatocellular Carcinoma

It is not clear how coffee consumption could inhibit liver damage or the development of cirrhosis and hepatocellular carcinoma. Consumption of unfiltered coffee and coffee oil containing cafestol and kahweol has been found to increase serum ALT and aspartate transaminase (AST) levels in human clinical trials.120,121 In contrast, cafestol and kahweol have been found to induce phase II enzyme activity, enhance hepatic glutathione levels and decrease liver DNA adducts caused by chemical carcinogens in animal models.93,95,96 In epidemiological studies, inverse associations between coffee consumption and the risk of cirrhosis and hepatocellular carcinoma have been observed in populations that drink mainly filtered and instant coffee with negligible concentrations of these diterpenes. Although other compounds in coffee, including caffeine and
chlorogenic acid, have been found to inhibit chemically induced hepatic carcinogenesis in animal models,122,123 more research is needed to determine the nature of the relationship between coffee and caffeine intake and hepatocellular carcinoma in humans.

POTENTIAL HEALTH RISKS OF COFFEE CONSUMPTION


Cardiovascular Disease

Coronary Heart Disease Risk
Several epidemiological studies have examined the relationship between coffee consumption and coronary heart disease (CHD) risk. In general, case-control studies have found high coffee intakes to be associated with significantly increased risk of CHDor myocardial infarction (MI).Two separate meta-analyses that combined the results of eight case-control studies found that CHD risk was 40–60% higher in those who consumed 5 or more cups of coffee daily compared to those who did not drink coffee.124,125 Since the publication of the last meta-analysis in 1994, several other case-control studies have found high coffee intakes (5–10 cups daily) to be associated with increased risk of MI,126–128 while two case-control studies found that more moderate coffee consumption (3–4 cups daily) was not associated with increased risk of MI.129,130 One case-control study in Greece found a J-shaped relationship between coffee intake levels and the risk of developing an acute coronary syndrome (MI or unstable angina).131 The odds of being diagnosed with an acute coronary syndrome were three times higher in people who drank at least 600 ml of coffee daily than in those who did not drink coffee, but the odds were significantly lower in people who consumed less than 300 ml daily than in those who did not drink coffee.

Prospective cohort studies have not generally found significant associations between coffee consumption and the risk of CHD. The results of two separate meta-analyses that combined the results of more than 10 prospective cohort studies did not support an association between coffee consumption and CHD risk.125,132 Similarly, most of the prospective cohort studies published since the last meta-analysis have not found significant associations between coffee consumption andCHDrisk, including studies of large cohorts in the US, Scotland, and Finland.2,32,133 Furthermore, a prospective cohort study in Norway that reported that coffee consumption dose-dependently increased the risk of CHD mortality after 6 years of follow-up found that CHD mortality risk was significantly increased only in those who consumed at least 9 cups daily after 12 years of follow-up.134

The investigators hypothesized that this may have been due to a decrease in the consumption of boiled coffee and a corresponding increase in the consumption of filtered coffee over time in Norway. Although limited by the potential for selection and recall bias, the results of most case-control studies suggest that people who consume 5 or more cups of coffee daily may be at increased risk of CHD. In contrast, the majority of prospective cohort studies have not found significant associations between coffee intake and CHD risk.

Established Coronary Heart Disease
The effect of coffee or caffeine consumption on people with established CHD has not been well studied. One case-control study found that heavy coffee consumption, defined as more than 10 cups daily, was associated with a significant increase in the risk of sudden cardiac arrest in patients with established coronary artery disease.135 However, a multicenter prospective study of 1935 patients who survived a MI found no association between coffee consumption and survival over the next 4 years, even in the heaviest coffee consumers.136 It should be noted that few patients reported consuming more than 10 cups of coffee daily in either study.


Cardiac Arrhythmias

Clinical trials have not found coffee or caffeine intake equivalent to 5–6 cups daily to increase the frequency or severity of cardiac arrhythmias in healthy people, CHD patients, or people with preexisting ventricular ectopy.137,138 A large prospective study in the US that followed more than 128,000 members of a health plan for 7 years found no association between coffee consumption and sudden cardiac death. More recently, two prospective studies in Scandinavia found no association between coffee consumption and the risk of developing atrial fibrillation, a common supraventricular arrhythmia.139,140

Stroke Risk

Few prospective cohort studies have specifically reported associations between coffee consumption and coffee consumption and the risk of stroke.141–143 One exception was a 25-year study of 499 nonsmoking hypertensive men enrolled in the Honolulu Heart Study. In that high-risk population, the risk of thromboembolic (ischemic) stroke in men who consumed at least 24 oz of coffee daily was double that of men who did not drink coffee.144 More research is needed to determine whether coffee consumption increases the risk of stroke in high-risk groups, such as individuals with hypertension.

Coffee Consumption and Cardiovascular Disease Risk Factors Serum Total and LDL Cholesterol.

A meta-analysis of 14 randomized controlled trials found that the consumption of boiled coffee dose-dependently increased serum total and LDL cholesterol concentrations, while the consumption of filtered coffee resulted in very little change in serum cholesterol.13

Overall, the consumption of boiled coffee increased serum total cholesterol by 23 mg/dl and LDL cholesterol by 14 mg/dl, while the consumption of filtered coffee raised total cholesterol by only 3 mg/dl and did not affect LDL cholesterol. The cholesterol-raising factors in unfiltered coffee have been identified as cafestol and kahweol (see above), diterpenes that are removed from coffee by paper filters.12

Plasma Total Homocysteine. An elevated plasma total homocysteine (tHcy) concentration is associated with an increased risk for cardiovascular disease, including CHD, stroke and peripheral vascular disease, but it is unclear whether the relationship is causal.145 Coffee consumption has been positively associated with tHcy concentrations in a dose-dependent manner in numerous cross-sectional studies conducted in Europe, Scandinavia and the US.146–150 Controlled clinical trials have confirmed the homocysteine-raising effect of relatively high intakes of coffee.151–153 Consumption of one liter of unfiltered (French press) coffee daily by healthy adults for 2 weeks raised fasting plasma tHcy concentrations by 10%, and consumption of one liter of filtered coffee daily raised fasting plasma tHcy concentrations by about 18%.152 Abstention from coffee consumption for 6 weeks resulted in an 11% decrease in fasting tHcy concentrations in those who consumed an average of 4 cups of filtered coffee daily.151 The results of controlled clinical trials suggest that caffeine and chlorogenic acid contribute to the homocysteine-raising effect of coffee.154,155 In a randomized, placebo-controlled crossover trial, supplementation of healthy men and women with 200 mcg/d of folic acid prevented elevations in plasma tHcy induced by the consumption of 600 ml/d of filtered coffee for 4 weeks.156 The effect of coffee consumption on plasma tHcy was most pronounced in those who were homozygous for the methionine tetrahydrofolate reductase (MTHFR) C677T polymorphism, but folic acid supplementation also prevented tHcy elevations in this group.157 Although it is not clear whether elevations in plasma tHcy related to coffee consumption actually increase the risk of cardiovascular disease, this effect may be prevented by adequate folate consumption or folic acid supplementation.

Hypertension. Hypertension is a recognized risk factor for CHD and stroke. It has been well-established that acute consumption of caffeine at dietary levels raises blood pressure in normotensive and hypertensive individuals.6 A 200–250-mg dose of caffeine, equivalent to the amount in 2–3 cups of coffee, has been found to increase systolic blood pressure by 3–14 mm Hg and to increase diastolic blood pressure by 4–13 mg Hg in normotensive individuals.158 This pressor effect of caffeine may be more pronounced in hypertensive individuals.158,159 Although habitual consumption has been found to result in a degree of tolerance to the pressor effect of caffeine, the results of several clinical trials suggest that this tolerance is not always complete even in those who consume caffeine daily.160–162 Two metaanalyses have examined the results of randomized controlled trials of coffee consumption for more than one week on blood pressure.163,164 A meta-analysis that included 11 randomized controlled trials, in which the median duration of coffee consumptionwas 56 days and the median intakewas 5 cups/d, found that coffee consumption significantly increased systolic and diastolic blood pressure by 2.4 and 1.2 mm Hg, respectively.163 More recently, a meta-analysis that included 18 randomized controlled trials with a median duration of 43 days and a median intake of 725 ml/d found that coffee consumption significantly increased systolic blood pressure by 1.2 mm Hg, but the increase in diastolic blood pressure of 0.5 mm Hg was not statistically significant.164 When the same investigators analyzed the results of seven randomized controlled trials of chronic caffeine consumption (median dose 410 mg/d), they found that caffeine significantly increased systolic and diastolic blood pressure by 4.2 and 2.4 mm Hg, respectively. It is not clear why the pressor response was greater when caffeine was administered in tablets compared to coffee. Overall, caffeine consumption from coffee was not less than from tablets, and caffeine is readily absorbed from coffee. However, it is possible that other compounds in coffee could attenuate the pressor effect of caffeine.

The effects of long-term coffee consumption on blood pressure and the risk of hypertension are less clear. Crosssectional studies of the relationships between coffee consumption and blood pressure in different populations have reported no association,165–167 positive associations168–171 and inverse associations.172–174 These inconsistent results could be related to measurement issues. For example, one study found that mean systolic and diastolic blood pressure differed significantly by 4 mm Hg and 2 mm Hg, respectively, between those who had consumed caffeine in the last 3 hours and those who had not consumed caffeine in the last nine hours.175 At the time most of these studies were conducted, people with high blood pressure were often advised to decrease coffee consumption.176 Thus, inverse associations between coffee and blood pressure could reflect selective reductions in coffee consumption by people with high blood pressure.177 Few prospective studies have reported on associations between coffee consumption and the risk of hypertension.

A 6-year study of 340 Australian men found that systolic blood pressure decreased significantly in those who reduced their coffee consumption.178 More recently, a prospective cohort study of 1017 men, who were followed for an average of 33 years, found that consumption of 1 cup of coffee daily raised systolic and diastolic blood pressure by an average of less than 1mmHg. However, men who drank coffee were not more likely than nondrinkers to develop hypertension over the next 33 years, after adjusting for other hypertension risk factors.177

The acute pressor effects of caffeine have been welldocumented, and the results of randomized controlled trials indicate that caffeinated coffee consumption for 1–12 weeks modestly raises systolic blood pressure by about 2 mm Hg. Although such an increase seems small by individual standards, it has been estimated that an average reduction of 2 mm Hg in population systolic blood pressure would result in 10% lower mortality from stroke and 7% lower mortality from CHD.179 The results of epidemiological studies of long-term coffee consumption are mixed, but generally suggest that any contribution of coffee consumption to the development of hypertension is likely to be small. However, additional prospective cohort studies are needed to clarify the relationships between long-term coffee and caffeine consumption and the risk of hypertension.

Cancer

Numerous epidemiological studies have examined relationships between coffee and caffeine intake and cancer risk in humans. In general, there is little evidence that coffee consumption increases the risk of cancer, especially when the analyses are adjusted for cigarette smoking.180 Although early case-control studies tended to show positive associations between caffeine intake and pancreatic, bladder and ovarian cancers, more recent and better-designed studies have not supported the hypothesis that coffee consumption contributes significantly to the risk of these cancers.181–183 In general, recent prospective cohort studies have not observed significant associations between caffeine or coffee intake and the risk of pancreatic, bladder, ovarian, breast, gastric and prostate cancer.182


Osteoporosis and Hip Fracture

The results of controlled calcium balance studies in humans indicate that caffeine consumption leads to a small negative calcium balance in individuals with inadequate calcium intakes.184 The negative shift in calcium balance has been estimated to be about 4–6 mg of calcium per cup of coffee, and is due to a slight decrease in the efficiency of calcium absorption.185,186 The majority of cross-sectional studies have found no association between caffeine consumption and bone mineral density (BMD).184 Of the six studies that have examined associations between caffeine consumption and change in BMD over time, four found no effect of caffeine.187–190 One found that the consumption of more than 300 mg/d was associated with accelerated loss of BMD,191 and another found that caffeine consumption was associated with accelerated loss of BMD only in women with calcium intakes less than 744 mg/d.192 Five case-control studies have examined relationships between coffee and caffeine consumption and the risk of hip fracture. None of them found coffee or caffeine consumption to be associated with significantly increased risk of hip fracture.193–197 Six prospective cohort studies have examined associations between caffeine (mainly from coffee) or coffee consumption and the risk of hip fracture in women. Two studies, one in Finland198 and one in Japan,199 found no association.
Another study in Norway found that women who consumed at least 9 cups of coffee daily tended to have an
increased risk of hip fracture, but only 6.8% ofwomen consumed this much coffee.200 However, three prospective cohort studies in the US found that coffee or caffeine consumption was positively associated with the risk of hip fracture in women.201–203 In the Framingham cohort, women who consumed more than 2 cups of coffee daily had a 70% higher risk of hip fracture over the next 12 years than women who did not consume caffeinated beverages.201 In the Nurses’ Health Study cohort, women who consumed 4 or more cups of coffee daily had a risk of hip fracture over the next 6 years that was almost three times the risk of those who did not drink coffee.202 A prospective cohort study of women 65 years of age and older found that a 190 mg increase in caffeine consumption increased the risk of osteoporotic fracture by about 20%.203 Given the multifactorial etiology of osteoporosis, the impact of coffee or caffeine consumption on the risk of osteoporosis is not clear. However, currently available evidence suggests that ensuring adequate calcium and vitamin D intake and limiting coffee consumption to 3 cups/d (300 mg/d of caffeine) may help reduce the risk of osteoporosis and osteoporotic fractures, particularly in older adults.

Mineral Deficiencies
Impaired Iron Absorption

Polyphenols in coffee can bind nonheme iron and inhibit its intestinal absorption.204 Drinking 150–250 ml of coffee with a test meal has been found to inhibit the absorption of iron by 24–73%.205–208 Discontinuing coffee consumption significantly improved the response to iron supplements in Guatemalan toddlers.209 To maximize iron absorption from a meal or iron supplements, concomitant intake of coffee should be avoided.

Impaired Zinc Absorption

Dietary inhibitors of zinc absorption, particularly phytate, increase the risk of zinc deficiency.210 Zinc chelating compounds have been identified in coffee,211 and coffee has been found to inhibit the bioavailability of zinc in vitro by 21–32%.212 The effect of coffee consumption on human zinc status has not been well studied. Although there is one report that coffee appeared to inhibit zinc absorption in human volunteers,213 discontinuation of coffee for 5 months did not affect plasma zinc levels in Guatemalan toddlers.209


SPECIAL RISK GROUPS

Women of Childbearing Age

Caffeine and Conception
Numerous epidemiological studies have examined the relationship between caffeine consumption and the time to conception (fecundability) in women who are not using contraception.180 Some epidemiological studies found no significant delay in time to conception associated with coffee or caffeine intakes.214–218 Other studies found that only high intakes of coffee or caffeine ranging from 400–800 mg/d were associated with significant delays in conception.219–223 Two studies found significant decreases in the monthly probability of pregnancy in women who consumed at least 300 mg of caffeine daily.224,225 Several of these studies have been criticized for failing to adequately control other lifestyle factors related to fertility, particularly cigarette smoking and alcohol consumption.31 Based on the available data from epidemiological studies, it may be for women who are having difficulty conceiving to limit caffeine consumption to less than 300 mg/d in addition tobacco use and decreasing alcohol consumption.

Caffeine and Pregnancy Complications

Spontaneous Abortion. The results of numerous epidemiological studies that have examined the relationship between maternal coffee or caffeine intake and the risk of spontaneous abortion have been conflicting. While some studies have observed significant associations between high caffeine intakes, particularly from coffee, and the risk of spontaneous abortion,226–230 other studies have not found significant associations.231,232 A number of methodological issues with these studies have been raised, including limitations in determining caffeine intake and confounding by other risk factors for miscarriage, such as nausea and smoking.28,31,233 Most studies that observed significant associations between self-reported coffee or caffeine consumption
and the risk of spontaneous abortion did so at intake levels of at least 300 mg/d of caffeine.180 In contrast, one study that assessed caffeine intake by measuring serum concentrations of paraxanthine, a caffeine metabolite, found that the risk of spontaneous abortion was only elevated in women with paraxanthine levels in the 95th percentile, suggesting a caffeine intake of at least 600 mg/d.234

It has been proposed that an association between caffeine consumption and the risk of spontaneous abortion could be explained by the relationship between nausea and fetal viability.31 Nausea is more common inwomen with viable pregnancies than nonviable pregnancies,235 suggesting that women with viable pregnancies are more likely to avoid or limit caffeine consumption due to nausea. However, at least one study found that the significant increase in the risk of spontaneous abortion observed in women with caffeine intakes higher than 300 mg/d was independent of nausea in pregnancy,228 and two other studies found that caffeine consumption was associated with increased risk of spontaneous abortion in women who experienced nausea or aversion to coffee during pregnancy.226,230 The authors of recent reviews of epidemiological studies focusing on methodological issues have concluded that a causal association between caffeine consumption and the risk of spontaneous abortion has not been demonstrated.31,233 Although the topic remains controversial, the available epidemiological evidence suggests that maternal consumption of less than 300 mg/d of caffeine is unlikely to
increase the risk of spontaneous abortion.

Fetal Growth. Epidemiological studies examining the effects of maternal caffeine consumption on fetal growth have assessed mean birth weight, low birth weight (less than 2500 g) and fetal growth retardation (less than the 10th percentile of birth weight for gestational age). Several studies found that maternal caffeine intakes ranging from 200–400 mg/d were associated with decreases in mean birth weight of about 100 g.28,236,237 A large prospective study found that caffeine consumption was associated with a small but significant reduction in mean birth weight (?28 g/100 mg caffeine), but the investigators concluded that this decrease was unlikely to be clinically important in women with caffeine intakes of less than 600 mg/d.238 Results of epidemiological studies examining the effect of maternal caffeine consumption on the risk of low birth weight and fetal growth retardation are conflicting. Maternal caffeine consumption has been positively associated with the risk of low birth weight in some,236,237,239–241 but not all epidemiological studies.30,238,242–249 A meta-analysis that combined the results of eight epidemiological studies found that maternal caffeine consumption greater than 150 mg/d increased the risk of low birth weight by approximately 50%.250 However, the investigators were not able to control for the effects of confounders in that meta-analysis. Maternal caffeine and coffee consumption have also been associated with increased risk of fetal growth retardation in some epidemiological studies,231,236,240,245,251–253 but not others.232,243,254,255 Arecent case-control study found that mothers of small for gestational age (SGA) infants had significantly higher caffeine intakes in the third trimester of pregnancy than mothers of non-SGA infants (mean caffeine intake 281 mg/d vs. 212 mg/d).253 Even after adjusting for other risk factors, such as smoking, high caffeine intakes were still associated with increased risk of delivering anSGAinfant, particularly if the infant was a boy. A number of the available epidemiological studies,have been criticized for inadequately controlling for important,risk factors for low birth weight and fetal growth retardation,,particularly smoking.31 Although the relationship between maternal caffeine consumption and fetal growth requires further clarification, it appears unlikely that caffeine intakes less than 300 mg/d will adversely affect fetal growth in nonsmoking women.

Preterm Delivery. Most epidemiological studies have not found coffee or caffeine consumption to be associated with the risk of preterm delivery.218,236,238,244,245,247–249,256
Birth Defects. Caffeine administration during pregnancy results in congenital malformations in a number of animal species, but usually only at doses that also cause maternal toxicity.257

The majority of epidemiological studies have not found maternal caffeine or coffee consumption to be associated with increased risk of congenital malformations.180,257 At present, there is no convincing evidence from epidemiological studies that maternal caffeine consumption ranging from 300– 1000 mg/d increases the risk of congenital malformations in humans.

Lactation

Caffeine is detectable in breast milk within 15 minutes of consumption and peaks at about one hour after consumption.258 After maternal caffeine consumption of up to 335 mg, the amount of caffeine available to the infant through breast milkwas estimated to be less than 2mg over a 24-hour period. Maternal caffeine consumption of 500 mg/d resulted in daily infant caffeine intakes ranging from 0.3–1.0 mg/kg of body weight.259 The American Academy of Pediatrics categorizes caffeine as a maternal medication that is usually compatible with breastfeeding.260 Although high maternal caffeine intakes have been reported to cause irritability and poor sleeping patterns in infants, no adverse effects have been reported with moderate maternal intake of caffeinated beverages equivalent to 2–3 cups of coffee daily.

Children
Research on the effects of caffeine consumption in children is limited, and most studies have focused on behavioral effects.261
Despite increasing concern by the public regarding caffeinated beverage intake in children and adolescents,262 there has been little research on the topic in the past decade. A meta-analysis of nine short-term clinical trials of caffeine in children, including four in normal children and five in children with attention deficit hyperactivity disorder (ADHD), found no significant adverse effects on cognition or behavior.263 In general, caffeine doses less than 3.0 mg/kg of body weight have not resulted in adverse effects in children in controlled clinical trials. However, higher doses have resulted in some behavioral effects, such as increased nervousness or anxiety and sleep disturbances.180 It is unclear whether caffeine has serious adverse effects in children, but concerns regarding its effects on the developing nervous system have led to recommendations in Canada that daily caffeine intake by children should be limited to 2.5 mg/kg of body,weight.264

Older Adults
Coffee is the most common source of caffeine in the elderly.265,266 There is limited evidence that older adults are more susceptible to the acute blood pressure-raising effects of caffeine.267,268 Because caffeine is distributed mainly through lean mass, and older adults have lower lean mass to adipose ratios than younger adults, a dose of caffeine expressed as mg/kg of body weight has the potential to result in higher plasma and tissue concentrations in older adults.269 Higher plasma caffeine concentrations could increase the risk of drug interactions since older adults are more likely to take one or more medications that interact with caffeine (see Drug Interactions below).
The risk of hip fracture increases with age, and the results of several prospective cohort studies suggest that high caffeine intakes may contribute to hip fracture risk, particularly in the presence of calcium and vitamin D insufficiency.270 Overall, there is some evidence to suggest that older adults are more susceptible to some adverse effects of caffeine than younger adults.

ADVERSE EFFECTS OF CAFFEINE

Acute Toxicity and Overdose

Fatal or life-threatening caffeine overdoses generally involve the ingestion of caffeine-containing medications.271,272 Oral doses of 5–50 g (mean 10 g) have resulted in fatalities in adults, and the lethal dose is estimated at 100–200 mg/kg of body weight. Ingestion of 15–30 mg/kg has resulted in significant toxicity. Symptoms of caffeine overdose may include agitation, delirium, seizures, dyspnea, cardiac arrhythmia, myoclonus, nausea, vomiting, hyperglycemia and hypokalemia.

Adverse Reactions
Adverse reactions to lower doses of caffeine, such as those that may be achieved through coffee consumption, include tachycardia, palpitations, insomnia, restlessness, nervousness, tremor, headache, abdominal pain, nausea, vomiting, diarrhea and diuresis.271,272

Withdrawal
Caffeine withdrawal symptoms have been documented in a number of case reports and experimental studies.273 Commonly reported caffeine withdrawal symptoms include headaches, fatigue, drowsiness, irritability, difficulty concentrating and depressed mood. Nausea and myalgia have also been reported.

Significant withdrawal symptoms have been observed at longterm intakes as low as 100 mg/d, although they are more common with higher intakes. Gradual withdrawal from caffeine appears less likely to result in withdrawal symptoms than abrupt withdrawal.274

Drug Interactions
Habitual caffeine consumption increases CYP1A2 activity, which has implications for the metabolism for a number of medications.7 Conversely, drugs that inhibit the activity of CYP1A2 interfere with the metabolism and elimination of caffeine, increasing the risk of toxic effects.275.

Drugs that Alter Caffeine Metabolism
The following medications may impair the hepatic metabolism of caffeine, decreasing its elimination and potentially increasing the risk of caffeine-related side effects:
cimetidine (Tagamet), disulfiram (Antabuse), estrogens, fluconazole (Diflucan), fluvoxamine (Luvox),mexiletine (Mexitil), quinolone class antibiotics and terbinafine (Lamisil).7 Phenytoin (Dilantin) and cigarette smoking increase the hepatic metabolism of caffeine, resulting in increased elimination and decreased plasma caffeine concentrations.271

Caffeine Effects on Other Drugs

Caffeine and other methylxanthines may enhance the effects and side effects of ?-adrenergic stimulating agents, such as epinephrine and albuterol.7 Caffeine could theoretically increase the risk of hypertensive crisis in individuals taking monoamine oxidase inhibitors.276 Caffeine may inhibit the hepatic metabolism of the antipsychotic medication, clozapine, potentially elevating serum clozapine levels and increasing the risk of toxicity. Caffeine consumption can decrease the elimination of theophylline, potentially increasing serum theophylline levels.

Caffeine has been found to decrease the systemic elimination of acetaminophen and to increase the bioavailability of aspirin, which may partially explain its efficacy in enhancing their analgesic effects. Caffeine may decrease serum concentrations of lithium by enhancing its elimination.

Considerations for future research
Assessment of the health risks and benefits of coffee and caffeine consumption requires reliable data on exposure to caffeine and other compounds in coffee. The identification of biomarkers that accurately reflect the consumption of bioactive compounds in coffee represents an important tool for studying relationships between coffee consumption and health-related endpoints.277
Serum or urinary measures of caffeine metabolites may be used to assess dietary exposure to caffeine. A study of pregnant women found that the measurement of serum paraxanthine was useful for distinguishing varying caffeine intakes.278
In that study, Pearson correlation coefficients between selfreported caffeine intake and serum paraxanthine concentrations (0.50–0.53) were comparable to reported correlations between cigarette smoking and serum cotinine concentrations. Assessment of urinary caffeine metabolites, such as 1-methylxanthine and 1,7-dimethyluric acid may also be useful for assessing dietary caffeine intake.8 Since chlorogenic acid or its metabolites may also contribute to the health effects of coffee, a reliable biomarker for coffee-derived polyphenol intake would be useful. Isoferulic acid has been identified as a specific metabolite of dietary caffeic acid derivatives, such as chlorogenic acid.279.

However, in a recent study, less than 7% of the variance in coffee intake was explained by urinary isoferulic acid excretion, suggesting that it has limited usefulness as a biomarker for coffee-derived polyphenol exposure.277
Genetic heterogeneity in a study population may mask associations between dietary exposures and chronic disease risk.280 Epidemiological studies that examine interactions between coffee or caffeine intake and genetic polymorphisms affecting the activity of phase I and phase II biotransformation enzymes could help clarify some of the effects of coffee consumption on human health. CYP1A2 plays a major role in caffeine metabolism (Figure 2), as well as the metabolic activation of potentially carcinogenic heterocyclic amines.281 Two genetic polymorphisms (CYP1A2*1C and CYP1A2*1F) have been identified that appear to alter the inducibility of CYP1A2.282,283 Recently, a small case-control study of Japanese women found that caffeine
intake was not associated with recurrent pregnancy loss when CYP1A2 genotype was not considered.284 However, in women who were homozygous for the CYP1A2*1F polymorphism, a genotype associated with high inducibility of CYP1A2, caffeine intake was positively associated with the risk of recurrent pregnancy loss. CYP2A6 plays a role in caffeine metabolism (Figure 2), as well as nicotine metabolism and the activation of procarcinogenic nitrosamines. A number of distinct polymorphisms of CYP2A6 that affect its activity have been identified, some of which may affect smoking behavior and cancer risk.285,286
Numerous polymorphisms of the gene for NAT2 that affect its acetylation activity have been reported.281 Individuals classified as “slow acetylators” are essentially unable to acetylate the primary caffeine metabolite, paraxanthine (Figure 2). Aromatic amines in cigarette smoke and foods are also acetylated by NAT2, and NAT2 polymorphisms have been found to modulate the risk of several cancers in humans, including bladder and colorectal cancer.287 Caffeic acid, a metabolite of chlorogenic acid, is extensively glucuronidated through the activity of intestinal and hepatic UDP-glucuronosyltransferases (UGT).288 Genetic polymorphisms have been described for 6 of the 16 human UGT genes, but functional significance has only been demonstrated for a polymorphism of UGT1A1.289 Future epidemiological studies that consider interactions between coffee intake and genetic polymorphisms may identify specific genotypes that are more susceptible to adverse effects of coffee consumption or more likely to experience health benefits related to coffee consumption.

Conclusions
Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine.18,265 Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterol-raising effects of coffee.12 The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 DM,41 Parkinson’s disease69 and liver disease.4 Large prospective cohort studies in the Netherlands, US, Finland and Sweden have found coffee consumption to be associated with significant dose-dependent reductions in the risk of developing type 2 DM, although the mechanisms are unclear.41 Several large prospective cohort studies have found that caffeine consumption from coffee and other beverages is inversely associated with the risk of Parkinson’s disease inmenand women who have never used postmenopausal estrogen.3,67,68.

The results of animal studies suggest that the ability of caffeine to block adenosine A2A-receptors in the brain may play a role in this protective effect.77 Epidemiological studies also suggest that coffee consumption is associated with decreased risk of hepatic injury, cirrhosis and hepatocellular carcinoma, although the mechanisms are not clear.4 Inverse associations between coffee consumption and colorectal cancer risk observed in case-control studies have not generally been confirmed in prospective cohort studies.81,82.

Most prospective cohort studies have not found that coffee consumption is associated with significantly increased risk of CHD or stroke.81,82 However, randomized controlled trials lasting up to 12 weeks have found that coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure6 and plasma tHcy.152,153.

At present, there is little evidence that coffee consumption increases the risk of cancer.182 Although most studies have not found coffee or caffeine consumption to be inversely associated with bone mineral density in women who consume adequate calcium, positive associations between caffeine consumption and hip fracture risk in three prospective cohort studies suggest that limiting coffee consumption to 3 cups/d (300 mg/d of caffeine) may help prevent osteoporotic fractures in older adults.201–203 Although epidemiological data on the effects of caffeine during pregnancy are conflicting, they raise concern regarding the potential for high intakes of coffee or caffeine to increase the risk of spontaneous abortion and impair fetal growth.180 Serious adverse effects from caffeine at the levels consumed from coffee are uncommon, but there is a potential for adverse interactions with a number of medications.7 Regular consumers of coffee and other caffeinated beverages may experience withdrawal symptoms, particularly if caffeine cessation is abrupt.273.

Overall, there is little evidence of health risks and some evidence of health benefits for adults consuming moderate amounts of coffee (3–4 cups/d providing 300–400 mg/d of caffeine). A review of the effects of caffeine on human health commissioned by Health Canada also concluded that moderate caffeine intakes up to 400 mg/d are not associated with adverse health effects in healthy adults.180 However, some groups, including people with hypertension and the elderly, may be more vulnerable to the adverse effects of caffeine.6,269 Currently available evidence suggests that it would be prudent for women who are pregnant, lactating, or planning to become pregnant to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine.180
Caffeinated soft drinks are the principal source of caffeine in the diets of children and adolescents in the US, although coffee consumption increases somewhat during adolescence.265,266.

Limited data from short-term clinical trials suggest that daily caffeine intakes of 3 mg/kg of body weight or more may haveadverse effects in children and adolescents. These findings aremthe basis for Health Canada’s recommendation that children should not consume more than 2.5 mg/d of caffeine per kg of body weight.180,264 Clearly, more research is needed to determine whether long-term caffeine consumption has adverse effects on the health of children and adolescents.

Acknowledgements

Funding for this review was provided by Unilever.

REFERENCES
[1] Spiller, M.A. 1998. The Chemical Components of Coffee. In: Caffeine. pp. 97–161. Spiller, G. A., Ed., CRC Press, Boca Raton.
[2] Willett,W.C., Stampfer, M.J., Manson, J.E. et al. 1996. Coffee consumption and coronary heart disease in women. A ten-year follow-up. JAMA., 275:458–462.
[3] Ascherio, A., Zhang, S.M., and Hernan, M.A. 2001. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann. Neurol., 50:56–63.
[4] La Vecchia, C. 2005. Coffee, liver enzymes, cirrhosis and liver cancer. J. Hepatol., 42:444–446.
[5] Salazar-Martinez, E.,Willett,W.C., Ascherio, A. et al. 2004. Coffee consumption and risk for type 2 diabetes mellitus. Ann. Intern. Med., 140:1–8.
[6] James, J.E. 2004. Critical review of dietary caffeine and blood pressure: A relationship that should be taken more seriously. Psychosom. Med., 66:63–71.
[7] Carrillo, J.A., and Benitez, J. 2000. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin. Pharmacokinet, 39:127–153.
[8] Crews, H.M., Olivier, L., andWilson, L.A. 2001. Urinary biomarkers for assessing dietary exposure to caffeine. Food Addit. Contam., 18:1075– 1087.
[9] Krul, C., and Hageman, G. 1998. Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase highperformance liquid chromatography. J. Chromatogr B Biomed Sci. Appl., 709:27–34.
[10] McCusker, R.R., Goldberger, B.A., and Cone, E.J. 2003. Caffeine content of specialty coffees. J. Anal. Toxicol., 27:520–522.
[11] Thelle, D.S., Heyden, S., and Fodor, J.G. 1987. Coffee and cholesterol inepidemiological and experimental studies. Atherosclerosis., 67:97–103.
[12] Urgert, R., and Katan, M.B. 1997. The cholesterol-raising factor from coffee beans. Annu. Rev. Nutr., 17:305–324.
[13] Jee, S.H., He, J., Appel, L.J. et al. 2001. Coffee consumption and serum lipids: A meta-analysis of randomized controlled clinical trials. Am. J. Epidemiol., 153:353–362. [14] Gross, G., Jaccaud, E., and Huggett, A.C. 1997. Analysis of the content of the diterpenes cafestol and kahweol in coffee brews. Food Chem. Toxicol., 35:547–554.
[15] Urgert, R., van derWeg, G., Kosmeijer-Schuil, T.G., van de Bovenkamp, P.,Hovenier, R., and Katan, M.B. 1995. Levels of the cholesterol-elevating diterpenes cafestol and kahweol in various coffee brews. J. Agric. Food Chem., 43:2167–2172.
[16] De Roos, B., Meyboom, S., Kosmeijer-Schuil, T.G., and Katan, M.B. 1998. Absorption and urinary excretion of the coffee diterpenes cafestol and kahweol in healthy ileostomy volunteers. J. Intern. Med., 244:451– 460.
[17] De Roos, B., Van Tol, A., Urgert, R. et al. 2000. Consumption of Frenchpresscoffee raises cholesteryl ester transfer protein activitylevels beforeLDL cholesterol in normolipidaemic subjects. J. Intern. Med., 248:211– 216.
[18] Clifford, M.N. 1999. Chlorogenic acids and other cinnamates–nature occurrence and dietary burden. J. Sci. Food Agric., 79:362–372.
[19] Olthof, M.R., Hollman, P.C., and Katan, M.B. 2001. Chlorogenic acidand caffeic acid are absorbed in humans. J. Nutr., 131:66–71.
[20] Olthof, M.R., Hollman, P.C., Buijsman, M.N. et al. 2003. Chlorogenicacid, quercetin-3-rutinoside and black tea phenols are extensively metabolizedin humans. J. Nutr., 133:1806–1814.
[21] Iwai, K., Kishimoto, N., Kakino, Y. et al. 2004. In vitro antioxidative effects and tyrosinase inhibitory activities of seven hydroxycinnamoyl derivatives in green coffee beans. J. Agric. Food Chem., 52:4893–4898.
[22] U.S. Department of Agriculture and Agricultural Research Service. 2004. USDA Nutrient Database for Standard Reference, Release 17.http://www.nal.usda.gov/fnic/foodcomp.
[23] Institute of Medicine. 1997. Magnesium. In: Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride., pp. 190– 249. National Academy Press, Washington D.C.
[24] Institute of Medicine. 2004. Potassium. In: Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate., pp. 173–246. National Academies Press, Washington, D. C.
[25] Adrian, J., and Frangne, R. 1991. Synthesis and availability of niacin in roasted coffee. Adv. Exp. Med. Biol., 289:49–59.
[26] Institute of Medicine. 1998. Niacin. In: Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline., pp. 123–149. National Academy Press, Washington D.C.
[27] Institute of Medicine. 2000. Vitamin E. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids., pp. 95–185. National Academy Press, Washington D.C.
[28] Bracken, M.B., Triche, E., Grosso, L. et al. 2002. Heterogeneity in assessing self-reports of caffeine exposure: Implications for studies of health effects. Epidemiology., 13:165–171.
[29] Joeres, R., Klinker, H., Heusler, H. et al. 1988. Influence of smoking on caffeine elimination in healthy volunteers and in patients with alcoholic liver cirrhosis. Hepatology., 8:575–579.
[30] Cook, D.G., Peacock, J.L., Feyerabend, C. et al. 1996. Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study. BMJ., 313:1358–1362.
[31] Leviton, A., and Cowan, L. 2002. A review of the literature relating caffeine consumption by women to their risk of reproductive hazards. Food Chem Toxicol., 40:1271–1310.
[32] Woodward, M., and Tunstall-Pedoe, H. 1999. Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality. J. Epidemiol Community Health., 53:481–487.
[33] Kubo Shlonsky, A., Klatsky, A.L., and Armstrong, M.A. 2003. Traits of persons who drink decaffeinated coffee. Ann. Epidemiol., 13:273–279.
[34] Carlsson, S., Hammar, N., Grill, V., and Kaprio, J. 2004. Coffee consumptionand risk of type 2 diabetes in Finnish twins. Int. J. Epidemiol.,33:616–617.
[35] Rosengren, A., Dotevall, A., Wilhelmsen, L., Thelle, D., and Johansson, S. 2004. Coffee and incidence of diabetes in Swedish women: aprospective 18-year follow-up study. J. Intern. Med., 255:89–95.
[36] Tuomilehto, J., Hu, G., and Bidel, S. 2004. Coffee consumption and risk of type 2 diabetes mellitus among middle-aged Finnish men and women. JAMA., 291:1213–1219.
[37] van Dam, R.M., and Feskens, E.J. 2002. Coffee consumption and risk of type 2 diabetes mellitus. Lancet., 360:1477–1478.
[38] Reunanen, A., Heliovaara, M., and Aho, K. 2003. Coffee consumption and risk of type 2 diabetes mellitus. Lancet., 361:702–703.
[39] Saremi, A., Tulloch-Reid, M., and Knowler, W.C. 2003. Coffee consumption and the incidence of type 2 diabetes. Diabetes Care., 26:2211– 2212.
[40] van Dam, R.M., Dekker, J.M., Nijpels, G. et al. 2004. Coffee consumption and incidence of impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes: the Hoorn Study. Diabetologia., 47:2152– 2159.
[41] van Dam, R.M., and Hu, F.B. 2005. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA., 294:97–104.
[42] Keijzers, G.B., De Galan, B.E., Tack, C.J., and Smits, P. 2002. Caffeine can decrease insulin sensitivity in humans. Diabetes Care., 25:364–369.
[43] Petrie, H.J., Chown, S.E., Belfie, L.M. et al. 2004. Caffeine ingestion increases the insulin response to an oral-glucose-tolerance test in obese men before and after weight loss. Am. J. Clin. Nutr., 80:22–28.
[44] Graham, T.E., Sathasivam, P., Rowland, M. et al. 2001. Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test. Can J. Physiol. Pharmacol., 79:559–565.
[45] Greer, F., Hudson, R., Ross, R., and Graham, T. 2001. Caffeine ingestion decreases glucose disposal during a hyperinsulinemic-euglycemic clamp in sedentary humans. Diabetes., 50:2349–2354.
[46] Naismith, D.J., Akinyanju, P.A., Szanto, S., and Yudkin, J. 1970. The effect, in volunteers, of coffee and decaffeinated coffee on blood glucose, insulin, plasma lipids and some factors involved in blood clotting. Nutr. Metab., 12:144–151.
[47] van Dam, R.M., Pasman, W.J., and Verhoef, P. 2004. Effects of coffee consumption on fasting blood glucose and insulin concentrations: randomized controlled trials in healthy volunteers. Diabetes Care., 27:2990– 2992.
[48] Yamaji, T., Mizoue, T., Tabata, S. et al. 2004. Coffee consumption and glucose tolerance status in middle-aged Japanese men. Diabetologia., 47:2145–2151.
[49] Soriguer, F., Rojo-Martinez, G., and de Antonio, I.E. 2004. Coffee consumption and type 2 diabetes mellitus. Ann. Intern. Med., 141:321-323; author reply 323–324.
[50] Agardh, E.E., Carlsson, S., Ahlbom, A. et al. 2004. Coffee consumption, type 2 diabetes and impaired glucose tolerance in Swedish men and women. J. Intern. Med., 255:645–652.
[51] Herling, A.W., Burger, H.J., Schwab, D. et al. 1998. Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system. Am. J. Physiol., 274:G1087–G1093.
[52] Arion, W.J., Canfield, W.K., Ramos, F.C. et al. 1997. Chlorogenic acid and hydroxynitrobenzaldehyde: New inhibitors of hepatic glucose 6-phosphatase. Arch. Biochem Biophys., 339:315–322.
[53] Welsch, C.A., Lachance, P.A., and Wasserman, B.P. 1989. Dietary phenolic compounds: Inhibition of Na+-dependent D-glucose uptake in rat intestinal brush border membrane vesicles. J. Nutr., 119:1698–1704.
[54] Johnston, K.L., Clifford, M.N., and Morgan, L.M. 2003. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: Glycemic effects of chlorogenic acid and caffeine. Am. J. Clin Nutr., 78:728–733.
[55] Meyer, K.A., Kushi, L.H., Jacobs, D.R., Jr. et al. 2000. Carbohydrates, dietary fiber, and incident type 2 diabetes in older women. Am. J. Clin Nutr., 71:921–930.
[56] Lopez-Ridaura, R., Willett, W.C., Rimm, E.B. et al. 2004. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care., 27:134–140.
[57] Kao, W.H., Folsom, A.R., Nieto, F.J. et al. 1999. Serum and dietary magnesium and the risk for type 2 diabetes mellitus: The Atherosclerosis Risk in Communities Study. Arch. Intern. Med., 159:2151–2159.
[58] Guerrero-Romero, F., Tamez-Perez, H.E., Gonzalez-Gonzalez, G. et al. 2004. Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab., 30:253–258.
[59] Rodriguez-Moran, M., and Guerrero-Romero, F. 2003. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care., 26:1147–1152.
[60] Paolisso, G., Sgambato, S., Gambardella, A. et al. 1992. Daily magnesium supplements improve glucose handling in elderly subjects. Am. J. Clin. Nutr., 55:1161–1167.
[61] Astrup, A., Toubro, S., Cannon, S. et al. 1990. Caffeine: A double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am. J. Clin Nutr., 51:759–767.
[62] Bracco, D., Ferrarra, J.M., Arnaud, M.J. et al. 1995. Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women. Am. J. Physiol., 269:E671–E678.
[63] Horton, T.J., and Geissler, C.A. 1996. Post-prandial thermogenesis with ephedrine, caffeine and aspirin in lean, pre-disposed obese and obese women. Int. J. Obes Relat Metab Disord., 20:91–97.
[64] Egger, G., Cameron-Smith, D., and Stanton, R. 1999. The effectiveness of popular, non-prescription weight loss supplements. Med. J. Aust., 171:604–608.
[65] Greenberg, J.A., Axen, K.V., Schnoll, R., and Boozer, C.N. 2005. Coffee, tea and diabetes: The role of weight loss and caffeine. Int. J. Obes Relat Metab Disord., 29:1121–1129.
[66] Hernan, M.A., Takkouche, B., Caamano-Isorna, F. et al. 2002. A meta-analysis of coffee drinking, cigarette smoking, and the risk of
Parkinson’s disease. Ann. Neurol., 52:276–284.
[67] Ross, G.W., Abbott, R.D., Petrovitch, H. et al. 2000. Association of coffee and caffeine intake with the risk of Parkinson disease.JAMA., 283:2674–2679.
[68] Ascherio, A., Weisskopf, M.G., O’Reilly, E.J. et al. 2004. Coffee consumption, gender, and Parkinson’s disease mortality in the cancer prevention study II cohort: The modifying effects of estrogen. Am. J. Epidemiol., 160:977–984.
[69] Ascherio, A., and Chen, H. 2003. Caffeinated clues from epidemiology of Parkinson’s disease. Neurology., 61:S51–S54.
[70] Ascherio, A., Chen, H., Schwarzschild, M.A. et al. 2003. Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology., 60:790–795.
[71] Pollock, B.G., Wylie, M., Stack, J.A. et al. 1999. Inhibition of caffeine metabolism by estrogen replacement therapy in postmenopausal women. J. Clin. Pharmacol., 39:936–940.
[72] Schwarzschild, M.A., Chen, J.F., and Ascherio, A. 2002. Caffeinated clues and the promise of adenosine A(2A) antagonists in PD. Neurology., 58:1154–1160.
[73] Eriksen, J.L., Wszolek, Z., and Petrucelli, L. 2005. Molecular pathogenesis of Parkinson disease. Arch. Neurol., 62:353–357.
[74] Fisone, G., Borgkvist, A., and Usiello, A. 2004. Caffeine as a psychomotor stimulant: mechanism of action. Cell. Mol. Life Sci., 61:857–872.
[75] Langston, J.W., Ballard, P., Tetrud, J.W., and Irwin, I. 1983. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science., 219:979–980.
[76] Chen, J.F., Xu, K., Petzer, J.P. et al. 2001. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J. Neurosci., 21:RC143.
[77] Schwarzschild, M.A., Xu, K., Oztas, E. et al. 2003. Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson’s disease. Neurology., 61:S55–S61.
[78] Kawachi, I.,Willett,W.C., Colditz, G.A. et al. 1996.Aprospective study of coffee drinking and suicide in women. Arch. Intern. Med., 156:521–525.
[79] Klatsky, A.L., Armstrong, M.A., and Friedman, G.D. 1993. Coffee, tea, and mortality. Ann. Epidemiol., 3:375–381.
[80] Tanskanen, A., Tuomilehto, J., Viinamaki, H. et al. 2000. Heavy coffee drinking and the risk of suicide. Eur. J. Epidemiol., 16:789–791.
[81] Tavani, A., and La Vecchia, C. 2004. Coffee, decaffeinated coffee, tea and cancer of the colon and rectum: A review of epidemiological studies, 1990-2003. Cancer Causes Control., 15:743–757.
[82] Giovannucci, E. 1998. Meta-analysis of coffee consumption and risk of colorectal cancer. Am. J. Epidemiol., 147:1043–1052.
[83] Michels, K.B., Willett, W.C., Fuchs, C.S., and Giovannucci, E. 2005. Coffee, tea, and caffeine consumption and incidence of colon and rectal cancer. J. Natl. Cancer Inst., 97:282–292.
[84] Olsen, J., and Kronborg, O. 1993. Coffee, tobacco and alcohol as risk factors for cancer and adenoma of the large intestine. Int. J. Epidemiol., 22:398–402.
[85] Lee,W.C., Neugut, A.I., Garbowski, G.C. et al. 1993. Cigarettes, alcohol, coffee, and caffeine as risk factors for colorectal adenomatous polyps. Ann. Epidemiol., 3:239–244.
[86] Kono, S., Shinchi, K., Ikeda, N. et al. 1991. Physical activity, dietary habits and adenomatous polyps of the sigmoid colon: A study of self-defense officials in Japan. J. Clin. Epidemiol., 44:1255–1261.
[87] Baron, J.A., Greenberg, E.R., Haile, R. et al. 1997. Coffee and tea and the risk of recurrent colorectal adenomas. Cancer Epidemiol Biomarkers Prev., 6:7–10.
[88] Grubben, M.J., Van Den Braak, C.C., Broekhuizen, R. et al. 2000. The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: A randomized trial. Aliment Pharmacol Ther., 14:1181–1190.
[89] Boekschoten, M.V., Hofman, M.K., Buytenhek, R. et al. 2005. Coffee oil consumption increases plasma levels of 7alpha-hydroxy-4-cholesten- 3-one in humans. J. Nutr., 135:785–789.
[90] Brown, S.R., Cann, P.A., and Read, N.W. 1990. Effect of coffee on distal colon function. Gut., 31:450–453.
[91] Dukas, L., Platz, E.A., Colditz, G.A. et al. 2000. Bowel movement, use of laxatives and risk of colorectal adenomatous polyps among women (United States). Cancer Causes Control., 11:907–914.
[92] Dukas, L., Willett, W.C., Colditz, G.A. et al. 2000. Prospective study of bowel movement, laxative use, and risk of colorectal cancer among women. Am. J. Epidemiol., 151:958–964.
[93] Cavin, C., Holzhaeuser, D., Scharf, G. et al. 2002. Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem. Toxicol., 40:1155–1163.
[94] Huber, W.W., McDaniel, L.P., Kaderlik, K.R. et al. 1997. Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat. Mutat. Res., 376:115–122.
[95] Huber,W.W., Prustomersky, S., Delbanco, E. et al. 2002. Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol. Arch. Toxicol., 76:209–217.
[96] Huber, W.W., Scharf, G., Rossmanith, W. et al. 2002. The coffee components kahweol and cafestol induce gamma-glutamylcysteine
synthetase, the rate limiting enzyme of chemoprotective glutathione synthesis, in several organs of the rat. Arch. Toxicol., 75:685–694.
[97] Friedman, S.L., and Schiano, T.D. 2004. Cirrhosis and its sequelae. In:Cecil. Textbook of Medicine., pp. 940-944. Goldman, L. and Ausiello, D., Eds., W.B. Saunders, St. Louis.
[98] Whitfield, J.B. 2001. Gamma glutamyl transferase. Crit. Rev. Clin. Lab. Sci., 38:263–355.
[99] Casiglia, E., Spolaore, P., Ginocchio, G., and Ambrosio, G.B. 1993. Unexpected effects of coffee consumption on liver enzymes. Eur. J. Epidemiol., 9:293–297.
[100] Honjo, S., Kono, S., Coleman, M. P. et al. 1999. Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan. Ann. Epidemiol., 9:325–331.
[101] Nakanishi, N., Nakamura, K., Nakajima, K. et al. 2000. Coffee consumption and decreased serum gamma-glutamyltransferase: a study of middle-aged Japanese men. Eur. J. Epidemiol., 16:419–423.
[102] Nilssen, O., Forde, O.H., and Brenn, T. 1990. The Tromso Study. Distribution and population determinants of gamma-glutamyltransferase.Am. J. Epidemiol., 132:318–326.
[103] Pintus, F., and Mascia, P. 1996. Distribution and population determinants of gamma-glutamyltransferase in a random sample of Sardinian inhabitants.‘ATS-SARDEGNA’ Research Group. Eur. J. Epidemiol., 12:71–76.
[104] Poikolainen, K., and Vartiainen, E. 1997. Determinants of gammaglutamyltransferase:positive interaction with alcohol and body mass index, negative association with coffee. Am. J. Epidemiol., 146:1019–1024.
[105] Sharp, D.S., and Benowitz, N.L. 1995. Re: “Alcohol, smoking, coffee, and cirrhosis” and “coffee and serum gamma-glutamyltransferase: A study of self-defense officials in Japan.”, Am. J. Epidemiol., 141:480–482.
[106] Tanaka, K., Tokunaga, S., Kono, S. et al. 1998. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int. J. Epidemiol., 27:438–443.
[107] Honjo, S., Kono, S., Coleman, M.P. et al. 2001. Coffee consumption and serum aminotransferases in middle-aged Japanese men. J. Clin. Epidemiol., 54:823–829.
[108] Ruhl, C.E., and Everhart, J.E. 2005. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology., 128:24–32.
[109] Cheng, W.S., Murphy, T.L., Smith, M.T. et al. 1990. Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function. Clin. Pharmacol Ther., 47:516–524.
[110] Wahllander, A., Renner, E., and Preisig, R. 1985. Fasting plasma caffeine concentration. A guide to the severity of chronic liver disease. Scand. J. Gastroenterol., 20:1133–1141.
[111] Corrao, G., Lepore, A.R., Torchio, P. et al. 1994. The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case-control study. Provincial Group for the Study of Chronic Liver Disease. Eur. J. Epidemiol., 10:657–664.
[112] Corrao, G., Zambon, A., Bagnardi, V. et al. 2001. Coffee, caffeine, and the risk of liver cirrhosis. Ann. Epidemiol., 11:458–465.
[113] Gallus, S., Tavani, A., Negri, E., and La Vecchia, C. 2002. Does coffee protect against liver cirrhosis? Ann. Epidemiol., 12:202–205.
[114] Klatsky, A.L., and Armstrong, M.A. 1992. Alcohol, smoking, coffee, and cirrhosis. Am. J. Epidemiol., 136:1248–1257.
[115] Tverdal, A., and Skurtveit, S. 2003. Coffee intake and mortality from liver cirrhosis. Ann. Epidemiol., 13:419–423.
[116] Gallus, S., Bertuzzi, M., Tavani, A. et al. 2002. Does coffee protect against hepatocellular carcinoma? Br. J. Cancer., 87:956–959.
[117] Gelatti, U., Covolo, L., Franceschini, M. et al. 2005. Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: A case-control study. J. Hepatol., 42:528–534.
[118] Inoue, M., Yoshimi, I., Sobue, T., and Tsugane, S. 2005. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: A prospective study in Japan. J. Natl. Cancer Inst., 97:293–300.
[119] Shimazu, T., Tsubono, Y., Kuriyama, S. et al. 2005. Coffee consumption and the risk of primary liver cancer: Pooled analysis of two prospective studies in Japan. Int. J. Cancer., 116:150–154.
[120] Boekschoten, M.V., Schouten, E.G., and Katan, M.B. 2004. Coffee bean extracts rich and poor in kahweol both give rise to elevation of liver enzymes in healthy volunteers. Nutr. J., 3:7.
[121] Urgert, R., Essed, N., van der Weg, G. et al. 1997. Separate effects of the coffee diterpenes cafestol and kahweol on serum lipids and liver aminotransferases. Am. J. Clin Nutr., 65:519–524.
[122] Hosaka, S., Kawa, S., Aoki, Y. et al. 2001. Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene. Food Chem. Toxicol., 39:557–561.
[123] Tanaka, T., Nishikawa, A., Shima, H. et al. 1990. Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters. Basic Life Sci., 52:429–440.
[124] Greenland, S. 1993. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology., 4:366–374.
[125] Kawachi, I., Colditz, G. A., and Stone, C. B. 1994. Does coffee drinking increase the risk of coronary heart disease? Results from a meta-analysis. Br. Heart J., 72:269–275.
[126] Hammar, N., Andersson, T., Alfredsson, L. et al. 2003. Association of boiled and filtered coffee with incidence of first nonfatal myocardial infarction: the SHEEP and the VHEEP study. J. Intern. Med., 253:653–659.
[127] Palmer, J.R., Rosenberg, L., Rao, R. S., and Shapiro, S. 1995. Coffee consumption and myocardial infarction in women. Am. J.Epidemiol., 141:724–731.
[128] Tavani, A., Bertuzzi, M., Negri, E. et al. 2001. Alcohol, smoking, coffee and risk of non-fatal acute myocardial infarction in Italy. Eur. J. Epidemiol., 17:1131–1137.
[129] Sesso, H.D., Gaziano, J.M., Buring, J.gE., and Hennekens, C.H. 1999. Coffee and tea intake and the risk of myocardial infarction. Am. J. Epidemiol., 149:162–167.
[130] Tavani, A., Bertuzzi, M., Gallus, S. et al. 2004. Risk factors for non-fatal acute myocardial infarction in Italian women. Prev. Med., 39:128–134.
[131] Panagiotakos, D.B., Pitsavos, C., Chrysohoou, C. et al. 2003. The J-shaped effect of coffee consumption on the risk of developing acute coronary syndromes: The CARDIO2000 case-control study. J. Nutr., 133:3228–3232.
[132] Myers, M.G., and Basinski, A. 1992. Coffee and coronary heart disease. Arch. Intern. Med., 152:1767–1772.
[133] Kleemola, P., Jousilahti, P., Pietinen, P. et al. 2000. Coffee consumption and the risk of coronary heart disease and death. Arch. Intern. Med., 160:3393–3400.
[134] Stensvold, I., Tverdal, A., and Jacobsen, B. K. 1996. Cohort study of coffee intake and death from coronary heart disease over 12 years. BMJ., 312:544–545.
[135] de Vreede-Swagemakers, J.J., Gorgels, A.P., Weijenberg, M.P. et al. 1999. Risk indicators for out-of-hospital cardiac arrest in patients with coronary artery disease. J. Clin Epidemiol., 52:601–607.
[136] Mukamal, K.J., Maclure, M., and Muller, J.E., 2004. Caffeinated coffee consumption and mortality after acute myocardial infarction. Am. Heart J., 147:999–1004.
[137] Chelsky, L.B., Cutler, J.E., Griffith, K. et al. 1990. Caffeine and ventricular arrhythmias. An electrophysiological approach. JAMA., 264:2236– 2240.
[138] Myers, M.G. 1991. Caffeine and cardiac arrhythmias. Ann. Intern. Med., 114:147–150.
[139] Frost, L., and Vestergaard, P. 2005. Caffeine and risk of atrial fibrillation or flutter: The Danish Diet, Cancer, and Health Study. Am. J. Clin Nutr., 81:578–582.
[140] Wilhelmsen, L., Rosengren, A., and Lappas, G. 2001. Hospitalizations for atrial fibrillation in the general male population: Morbidity and risk factors. J. Intern. Med., 250:382–389.
[141] Adolfsson, R., Svardsudd, K., and Tibblin, G. 1977. 1913 men study—a longitudinal study of the development of stroke in a population. Scand. J. Soc. Med. Suppl., 14:122–127.
[142] Grobbee, D.E., Rimm, E.B., Giovannucci, E. et al. 1990. Coffee, caffeine, and cardiovascular disease in men. N. Engl. J. Med., 323:1026–1032.
[143] Heyden, S., Tyroler, H.A., Heiss, G. et al. 1978. Coffee consumption and mortality. Total mortality, stroke mortality, and coronary heart disease mortality. Arch. Intern. Med., 138:1472–1475.
[144] Hakim, A.A., Ross, G.W., Curb, J.D. et al. 1998. Coffee consumption in hypertensive men in older middle-age and the risk of stroke: The Honolulu Heart Program. J. Clin. Epidemiol., 51:487–494.
[145] Splaver, A., Lamas, G.A., and Hennekens, C.H. 2004. Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials. Am. Heart J., 148:34–40.
[146] Husemoen, L.L., Thomsen, T.F., Fenger, M., and Jorgensen, T. 2004. Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7)., Eur. J. Clin. Nutr., 58:1142–1150.
[147] Mennen, L.I., de Courcy, G.P., Guilland, J.C. et al. 2002. Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study. Am. J. Clin. Nutr., 76:1279–1289.
[148] de Bree, A., Verschuren, W.M., Blom, H.J., and Kromhout, D. 2001. Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am. J. Epidemiol., 154:150–154.
[149] Stolzenberg-Solomon, R.Z., Miller, E.R., 3rd, Maguire, M.G. et al. 1999. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am. J. Clin Nutr., 69:467–475.
[150] Nygard, O., Refsum, H., Ueland, P.M. et al., 1997. Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am. J. Clin Nutr., 65:136–143.
[151] Christensen, B., Mosdol, A., Retterstol, L. et al. 2001. Abstention from filtered coffee reduces the concentrations of plasma homocysteine and serum cholesterol–a randomized controlled trial. Am. J. Clin Nutr., 74:302–307.
[152] Urgert, R., van Vliet, T., Zock, P. L., and Katan, M. B. 2000. Heavy coffee consumption and plasma homocysteine: A randomized controlled trial in healthy volunteers. Am. J. Clin Nutr., 72:1107–1110.
[153] Grubben, M.J., Boers, G.H., Blom, H.J. et al. 2000. Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial. Am. J. Clin Nutr., 71:480–484.
[154] Verhoef, P., Pasman, W.J., Van Vliet, T. et al. 2002. Contribution of caffeine to the homocysteine-raising effect of coffee: a randomized controlled trial in humans. Am. J. Clin Nutr., 76:1244–1248.
[155] Olthof, M.R., Hollman, P.C., Zock, P.L., and Katan, M.B. 2001. Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am. J. Clin Nutr., 73:532–538.
[156] Strandhagen, E., Landaas, S., and Thelle, D.S. 2003. Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. Eur. J. Clin Nutr., 57:1411–1417.
[157] Strandhagen, E., Zetterberg, H., Aires, N. et al. 2004. The methylenetetrahydrofolate reductase C677T polymorphism is a major determinant of coffee-induced increase of plasma homocysteine: A randomized placebo controlled study. Int. J. Mol. Med., 13:811–815.
[158] Nurminen, M.L., Niittynen, L., Korpela, R., and Vapaatalo, H. 1999. Coffee, caffeine and blood pressure: a critical review. Eur. J. Clin. Nutr., 53:831–839.
[159] Hartley, T.R., Sung, B.H., and Pincomb, G.A. 2000. Hypertension risk status and effect of caffeine on blood pressure. Hypertension., 36:137–141.
[160] Denaro, C.P., Brown, C.R., Jacob, P., 3rd, and Benowitz, N.L. 1991. Effects of caffeine with repeated dosing. Eur. J. Clin. Pharmacol., 40:273–278.
[161] James, J.E. 1994. Chronic effects of habitual caffeine consumption on laboratory and ambulatory blood pressure levels. J. Cardiovasc Risk., 1:159–164.
[162] Lovallo, W.R., Wilson, M.F., Vincent, A.S. et al. 2004. Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension., 43:760–765.
[163] Jee, S.H., He, J., Whelton, P.K. et al. 1999. The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension., 33:647–652.
[164] Noordzij, M., Uiterwaal, C.S., Arends, L.R. et al. 2005. Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J. Hypertens., 23:921–928.
[165] Dawber, T.R., Kannel, W.B., and Gordon, T. 1974. Coffee and cardiovascular disease. Observations from the framingham study. N. Engl. J. Med., 291:871–874.
[166] Bertrand, C.A., Pomper, I., Hillman, G. et al. 1978. No relation between coffee and blood pressure. N. Engl. J. Med., 299:315–316.
[167] Lancaster, T., Muir, J., and Silagy, C. 1994. The effects of coffee on serum lipids and blood pressure in aUKpopulation. J. R. Soc. Med., 87:506–507.
[168] Lang, T., Degoulet, P., Aime, F. et al. 1983. Relation between coffee drinking and blood pressure: Analysis of 6,321 subjects in the Paris region. Am. J. Cardiol., 52:1238–1242.
[169] Lang, T., Bureau, J.F., Degoulet, P., Salah, H., and Benattar, C. 1983. Blood pressure, coffee, tea and tobacco consumption: an epidemiological study in Algiers. Eur. Heart. J., 4:602–607.
[170] Birkett, N.J., and Logan, A.G. 1988. Caffeine-containing beverages and the prevalence of hypertension. J. Hypertens Suppl., 6:S620–S622.
[171] Burke, V., Beilin, L.J., German, R. et al. 1992. Association of lifestyle and personality characteristics with blood pressure and hypertension: A cross-sectional study in the elderly. J. Clin. Epidemiol., 45:1061–1070.
[172] Periti, M., Salvaggio, A., Quaglia, G., and Di Marzio, L. 1987. Coffee consumption and blood pressure: An Italian study. Clin. Sci. (Lond). 72:443–447.
[173] Stensvold, I., Tverdal, A., and Foss, O. P. 1989. The effect of coffee on blood lipids and blood pressure. Results from a Norwegian cross-sectional study, men and women, 40–42 years. J. Clin. Epidemiol., 42:877–884.
[174] Salvaggio, A., Periti, M., Miano, L., and Zambelli, C. 1990. Association between habitual coffee consumption and blood pressure levels. J. Hypertens., 8:585–590.
[175] Shirlow, M.J., Berry, G., and Stokes, G. 1988. Caffeine consumption and blood pressure: an epidemiological study. Int. J. Epidemiol., 17:90–97.
[176] Hughes, J.R., Amori, G., and Hatsukami, D.K. 1988. A survey ofphysician advice about caffeine. J. Subst. Abuse., 1:67–70.
[177] Klag, M.J., Wang, N.Y., Meoni, L.A. et al. 2002. Coffee intake and risk of hypertension: The Johns Hopkins precursors study. Arch. Intern. Med., 162:657–662.
[178] Jenner, D.A., Puddey, I.B., Beilin, L.J., and Vandongen, R. 1988. Lifestyle- and occupation-related changes in blood pressure over a sixyear period in a cohort ofworking men. J. Hypertens Suppl., 6:S605–S607.
[179] Lewington, S., Clarke, R., Qizilbash, N. et al. 2002. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet., 360:1903–1913.
[180] Nawrot, P., Jordan, S., Eastwood, J. et al. 2003. Effects of caffeine on human health. Food Addit. Contam., 20:1–30.
[181] Leviton, A. 1990. Methylxanthine consumption and the risk of ovarian malignancy. Cancer. Lett., 51:91–101.
[182] Tavani, A. and La Vecchia, C. 2000. Coffee and cancer: a review of epidemiological studies, 1990–1999. Eur. J. Cancer Prev., 9:241–256.
[183] Zeegers, M.P., Kellen, E., Buntinx, F., and van den Brandt, P.A. 2004. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J. Urol., 21:392–401.
[184] Heaney, R.P. 2002. Effects of caffeine on bone and the calcium economy. Food Chem. Toxicol., 40:1263–1270.
[185] Barger-Lux, M.J., and Heaney, R.P. 1995. Caffeine and the calcium economy revisited. Osteoporos Int., 5:97–102.
[186] Hasling, C., Sondergaard, K., Charles, P., and Mosekilde, L. 1992. Calcium metabolism in postmenopausal osteoporotic women is determined by dietary calcium and coffee intake. J. Nutr., 122:1119–1126.
[187] Hannan, M.T., Felson, D.T., Dawson-Hughes, B. et al. 2000. Risk factors for longitudinal bone loss in elderly men and women: The Framingham Osteoporosis Study. J. Bone Miner Res., 15:710–720.
[188] Lloyd, T., Johnson-Rollings, N., Eggli, D.F. et al. 2000. Bone status among postmenopausal women with different habitual caffeine intakes: a longitudinal investigation. J. Am. Coll Nutr., 19:256–261.
[189] Lloyd, T., Rollings, N.J., Kieselhorst, K. et al. 1998. Dietary caffeine intake is not correlated with adolescent bone gain. J. Am. Coll Nutr., 17:454–457.
[190] Reid, I.R., Ames, R.W., Evans, M.C. et al. 1994. Determinants of the rate of bone loss in normal postmenopausal women. J. Clin. Endocrinol Metab., 79:950–954.
[191] Rapuri, P.B., Gallagher, J.C., Kinyamu, H.K., and Ryschon, K.L. 2001. Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes. Am. J. Clin. Nutr., 74:694–700.
[192] Harris, S.S. and Dawson-Hughes, B. 1994. Caffeine and bone loss in healthy postmenopausal women. Am. J. Clin. Nutr., 60:573–578.
[193] Nieves, J.W., Grisso, J.A., and Kelsey, J.L. 1992. A case-control study of hip fracture: Evaluation of selected dietary variables and teenage physical activity. Osteoporos Int., 2:122–127.
[194] Tavani, A., Negri, E., and La Vecchia, C. 1995. Coffee intake and risk of hip fracture in women in northern Italy. Prev. Med., 24:396–400.
[195] Cumming, R.G., and Klineberg, R.J. 1994. Case-control study of risk factors for hip fractures in the elderly. Am. J. Epidemiol., 139:493–503.
[196] Kanis, J., Johnell, O., Gullberg, B. et al. 1999. Risk factors for hip fracture in men from southern Europe: the MEDOS study. Mediterranean Osteoporosis Study. Osteoporos Int., 9:45–54.
[197] Johnell, O., Gullberg, B., Kanis, J.A. et al. 1995. Risk factors for hip fracture in European women: The MEDOS Study. Mediterranean Osteoporosis Study. J. Bone Miner. Res., 10:1802–1815.
[198] Huopio, J., Kroger, H., Honkanen, R. et al. 2000. Risk factors for perimenopausal fractures: a prospective study. Osteoporos Int., 11:219– 227.
[199] Fujiwara, S., Kasagi, F., Yamada, M., and Kodama, K. 1997. Risk factors for hip fracture in a Japanese cohort. J. Bone. Miner. Res., 12:998–1004.
[200] Meyer, H.E., Pedersen, J.I., Loken, E.B., and Tverdal, A. 1997. Dietary factors and the incidence of hip fracture in middle-aged Norwegians. A prospective study. Am. J. Epidemiol., 145:117–123.
[201] Kiel, D.P., Felson, D.T., Hannan, M.T et al. 1990. Caffeine and the risk of hip fracture: The Framingham Study. Am. J. Epidemiol., 132:675– 684.
[202] Hernandez-Avila, M., Colditz, G. A., Stampfer, M. J. et al. 1991. Caffeine, moderate alcohol intake, and risk of fractures of the hip and forearm in middle-aged women. Am. J. Clin Nutr., 54:157–163.
[203] Cummings, S.R., Nevitt, M.C., Browner,W.S. et al. 1995. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N. Engl. J. Med., 332:767–773.
[204] Fairweather-Tait, S.J. 2004. Iron nutrition in the UK: Getting the balance right. Proc. Nutr. Soc., 63:519–528.
[205] Hallberg, L. and Rossander, L. 1982. Effect of different drinks on the absorption of non-heme iron from composite meals. Hum. Nutr. Appl. Nutr., 36:116–123.
[206] Morck, T.A., Lynch, S.R., and Cook, J.D. 1983. Inhibition of food iron absorption by coffee. Am. J. Clin. Nutr., 37:416–420.
[207] Derman, D., Sayers, M., Lynch, S. R. et al. 1977. Iron absorption from a cereal-based meal containing cane sugar fortified with ascorbic acid. Br. J. Nutr., 38:261–269.
[208] Brune, M., Rossander, L., and Hallberg, L. 1989. Iron absorption and phenolic compounds: importance of different phenolic structures. Eur. J.Clin. Nutr., 43:547–557.
[209] Dewey, K.G., Romero-Abal, M.E., Quan de Serrano, J. et al. 1997. Effects of discontinuing coffee intake on iron status of iron-deficient Guatemalan toddlers: a randomized intervention study. Am. J. Clin. Nutr., 66:168–176.
[210] Institute of Medicine and Food and Nutrition Board. 2001. Zinc. In: Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. pp. 442–501. National Academy Press, Washington D.C.
[211] Wen, X., Enokizo, A., Hattori, H. et al. 2005. Effect of roasting on properties of the zinc-chelating substance in coffee brews. J. Agric. Food Chem., 53:2684–2689.
[212] Van Dyck, K., Tas, S., Robberecht, H., and Deelstra, H. 1996. The influence of different food components on the in vitro availability of iron, zinc and calcium from a composed meal. Int. J. Food Sci. Nutr., 47:499–506.
[213] Pecoud, A., Donzel, P., and Schelling, J.L. 1975. Effect of foodstuffs on the absorption of zinc sulfate. Clin. Pharmacol Ther., 17:469–474.
[214] Alderete, E., Eskenazi, B., and Sholtz, R. 1995. Effect of cigarette smoking and coffee drinking on time to conception. Epidemiology., 6:403–408.
[215] Caan, B., Quesenberry, C.P., Jr., and Coates, A.O. 1998. Differences in fertility associated with caffeinated beverage consumption. Am. J. Public Health., 88:270–274.
[216] Hakim, R.B., Gray, R.H., and Zacur, H. 1998. Alcohol and caffeine consumption and decreased fertility. Fertil Steril., 70:632–637.
[217] Joesoef, M.R., Beral,V., Rolfs, R.T. et al. 1990. Are caffeinated beverages risk factors for delayed conception? Lancet., 335:136–137.
[218] Olsen, J., Overvad, K., and Frische, G. 1991. Coffee consumption, birthweight, and reproductive failures. Epidemiology., 2:370–374.
[219] Bolumar, F., Olsen, J., Rebagliato, M., and Bisanti, L. 1997. Caffeine intake and delayed conception: a European multicenter study on infertility and subfecundity. European Study Group on Infertility Subfecundity. Am. J. Epidemiol., 145:324–334.
[220] Christianson, R.E., Oechsli, F.W., and van den Berg, B.J. 1989. Caffeinated beverages and decreased fertility. Lancet., 1:378.
[221] Florack, E.I., Zielhuis, G.A., and Rolland, R. 1994. Cigarette smoking, alcohol consumption, and caffeine intake and fecundability. Prev. Med., 23:175–180.
[222] Hassan, M.A., and Killick, S.R. 2004. Negative lifestyle is associated with a significant reduction in fecundity. Fertil. Steril., 81:384–392.
[223] Williams, M.A., Monson, R.R., Goldman, M.B. et al. 1990. Coffee and delayed conception. Lancet., 335:1603.
[224] Jensen, T.K., Henriksen, T.B., Hjollund, N.H. et al. 1998. Caffeine intake and fecundability: A follow-up study among 430 Danish couples planning their first pregnancy. Reprod Toxicol., 12:289–295.
[225] Stanton, C.K., and Gray, R.H. 1995. Effects of caffeine consumption on delayed conception. Am. J. Epidemiol., 142:1322–1329.
[226] Cnattingius, S., Signorello, L.B., Anneren, G. et al. 2000. Caffeine intake and the risk of first-trimester spontaneous abortion. N. Engl. J. Med., 343:1839–1845.
[227] Dlugosz, L., Belanger, K., Hellenbrand, K. et al. 1996. Maternal caffeine consumption and spontaneous abortion: a prospective cohort study. Epidemiology., 7:250–255.
[228] Giannelli, M., Doyle, P., Roman, E., Pelerin, M., and Hermon, C. 2003. The effect of caffeine consumption and nausea on the risk of miscarriage. Paediatr. Perinat. Epidemiol., 17:316–323.
[229] Rasch, V. 2003. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion. Acta. Obstet. Gynecol. Scand., 82:182– 188.
[230] Wen, W., Shu, X.O., Jacobs, D.R., Jr., and Brown, J.E. 2001. The associations of maternal caffeine consumption and nausea with spontaneous abortion. Epidemiology., 12:38–42.
[231] Fenster, L., Hubbard, A.E., Swan, S.H. et al. 1997. Caffeinated beverages, decaffeinated coffee, and spontaneous abortion. Epidemiology., 8:515–523.
[232] Mills, J.L., Holmes, L.B., Aarons, J.H. et al. 1993. Moderate caffeine use and the risk of spontaneous abortion and intrauterine growth retardation. JAMA., 269:593–597.
[233] Signorello, L.B., and McLaughlin, J.K. 2004. Maternal caffeine consumption and spontaneous abortion: A review of the epidemiologic evidence. Epidemiology., 15:229–239.
[234] Klebanoff, M.A., Levine, R.J., DerSimonian, R. et al. 1999. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N. Engl. J. Med., 341:1639–1644.
[235] Furneaux, E.C., Langley-Evans, A.J., and Langley-Evans, S.C. 2001.,Nausea and vomiting of pregnancy: Endocrine basis and contribution to pregnancy outcome. Obstet. Gynecol. Surv., 56:775–782.
[236] Martin, T.R., and Bracken, M.B. 1987. The association between low birth weight and caffeine consumption during pregnancy. Am. J. Epidemiol., 126:813–821.
[237] Peacock, J.L., Bland, J.M., and Anderson, H.R. 1991. Effects on birthweight of alcohol and caffeine consumption in smoking women. J. Epidemiol. Community Health., 45:159–163.
[238] Bracken, M.B., Triche, E.W., Belanger, K. et al. 2003. Association of maternal caffeine consumption with decrements in fetal growth. Am. J. Epidemiol., 157:456–466.
[239] Beaulac-Baillargeon, L., and Desrosiers, C. 1987. Caffeine-cigarette interaction on fetal growth. Am. J. Obstet Gynecol., 157:1236–1240.
[240] McDonald, A.D., Armstrong, B.G., and Sloan, M. 1992. Cigarette, alcohol, and coffee consumption and prematurity. Am. J. Public Health., 82:87–90.
[241] Vlajinac, H.D., Petrovic, R.R., Marinkovic, J.M. et al. 1997. Effect of caffeine intake during pregnancy on birth weight. Am. J. Epidemiol., 145:335–338.
[242] Caan, B.J., and Goldhaber, M.K. 1989. Caffeinated beverages and low birthweight: a case-control study. Am. J. Public Health., 79:1299– 1300.
[243] Eskenazi, B., Stapleton, A.L., Kharrazi, M., and Chee, W.Y. 1999. Associations between maternal decaffeinated and caffeinated coffee consumption and fetal growth and gestational duration. Epidemiology., 10:242–249.
[244] Fenster, L., Eskenazi, B.,Windham, G.C., and Swan, S.H. 1991. Caffeine consumption during pregnancy and fetal growth. Am. J.Public Health., 81:458–461.
[245] Fortier, I., Marcoux, S., and Beaulac-Baillargeon, L. 1993. Relation of caffeine intake during pregnancy to intrauterine growth retardation and preterm birth. Am. J. Epidemiol., 137:931–940.
[246] Larroque, B., Kaminski, M., and Lelong, N. 1993. Effects of birth weight of alcohol and caffeine consumption during pregnancy. Am. J. Epidemiol., 137:941–950.
[247] Linn, S., Schoenbaum, S.C., Monson, R.R. et al. 1982. No association between coffee consumption and adverse outcomes of pregnancy. N. Engl. J. Med., 306:141–145.
[248] Santos, I.S., Victora, C.G., Huttly, S., and Carvalhal, J.B. 1998. Caffeine intake and low birth weight: a population-based case-control study. Am. J. Epidemiol., 147:620–627.
[249] Shu, X.O., Hatch, M.C., Mills, J. et al. 1995. Maternal smoking, alcohol drinking, caffeine consumption, and fetal growth: results from a prospective study. Epidemiology., 6:115–120.
[250] Fernandes, O., Sabharwal, M., Smiley, T. et al. 1998. Moderate to heavy caffeine consumption during pregnancy and relationship to spontaneous abortion and abnormal fetal growth: A meta-analysis. Reprod. Toxicol., 12:435–444.
[251] Furuhashi, N., Sato, S., Suzuki, M. et al. 1985. Effects of caffeine ingestion during pregnancy. Gynecol. Obstet. Invest., 19:187–191.
[252] Rondo, P.H., Rodrigues, L.C., and Tomkins, A.M. 1996. Coffee consumption and intrauterine growth retardation in Brazil. Eur. J. Clin. Nutr., 50:705–709.
[253] Vik, T., Bakketeig, L.S., Trygg, K.U., Lund-Larsen, K., and Jacobsen, G. 2003. High caffeine consumption in the third trimester of pregnancy: Gender-specific effects on fetal growth. Paediatr. Perinat. Epidemiol., 17:324–331.
[254] Fried, P.A., and O’Connell, C.M. 1987. A comparison of the effects of prenatal exposure to tobacco, alcohol, cannabis and caffeine on birth size and subsequent growth. Neurotoxicol Teratol., 9:79–85.
[255] Grosso, L.M., Rosenberg, K.D., Belanger, K. et al. 2001. Maternal caffeine intake and intrauterine growth retardation. Epidemiology., 12:447–455.
[256] Berkowitz, G.S., Holford, T.R., and Berkowitz, R.L. 1982. Effects of cigarette smoking, alcohol, coffee and tea consumption on preterm delivery. Early. Hum. Dev., 7:239–250.
[257] Christian, M.S., and Brent, R.L. 2001. Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Teratology., 64:51–78.
[258] Berlin, C.M., Jr., Denson, H.M., Daniel, C.H., and Ward, R.M. 1984.
Disposition of dietary caffeine in milk, saliva, and plasma of lactating
women. Pediatrics., 73:59–63.
[259] Ryu, J.E. 1985. Caffeine in human milk and in serum of breast-fed
infants. Dev. Pharmacol. Ther., 8:329–337.
[260] American Academy of Pediatrics Committee on Drugs. 2001. Transfer of drugs and other chemicals into human milk. Pediatrics., 108:776– 789.
[261] Castellanos, F.X., and Rapoport, J.L. 2002. Effects of caffeine on development and behavior in infancy and childhood: A review of the published literature. Food Chem. Toxicol., 40:1235–1242.
[262] 2003. Caffeinated kids. Consum Rep., 68:28–29.
[263] Stein, M.A., Krasowski, M., Leventhal, B.L. et al. 1996. Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch. Pediatr. Adolesc. Med., 150:284–288.
[264] Health Canada. 2003. Fact Sheet Caffeine and Your Health. http://www.hc-sc.gc.ca/food-aliment/dg/e caffeine.html.
[265] Frary, C.D., Johnson, R.K., and Wang, M.Q. 2005. Food sources and intakes of caffeine in the diets of persons in the United States. J. Am. Diet Assoc., 105:110–113.
[266] Knight, C.A., Knight, I., Mitchell, D.C., and Zepp, J.E. 2004. Beverage caffeine intake in US consumers and subpopulations of interest: estimates from the Share of Intake Panel survey. Food Chem. Toxicol., 42:1923–1930.
[267] Arciero, P.J., Gardner, A.W., Benowitz, N.L., and Poehlman, E.T. 1998. Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion. Eur. J. Clin. Nutr., 52:805–812.
[268] Izzo, J.L., Jr., Ghosal, A., Kwong, T. et al. 1983. Age and prior caffeine use alter the cardiovascular and adrenomedullary responses to oral caffeine. Am. J. Cardiol., 52:769–773.
[269] Massey, L.K. 1998. Caffeine and the elderly. Drugs Aging., 13:43–50.
[270] Massey, L.K. 2001. Is caffeine a risk factor for bone loss in the elderly? Am. J. Clin Nutr., 74:569–570.
[271] 2005. CNS Stimulants: Caffeine. In: Drug Facts and Comparisons.,pp. 917–919. Novak, K., Ed., Wolters Kluwer Health, St. Louis.
[272] Engebretsen, K.M. and Harris, C. R. 2001. Caffeine and Related Nonprescription Sympathomimetics. In: Clin.ical Toxicology., pp. 310–315. Ford, M. D., et al. (Eds.), W. B. Saunders, Philadelphia.
[273] Juliano, L.M. and Griffiths, R.R. 2004. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl)., 176:1–29.
[274] Dews, P.B., Curtis, G.L., Hanford, K.J., and O’Brien, C.P. 1999. The frequency of caffeine withdrawal in a population-based survey and in a controlled, blinded pilot experiment. J. Clin. Pharmacol., 39:1221–,1232.
[275] Faber, M.S., and Fuhr, U. 2004. Time response of cytochrome P450,1A2 activity on cessation of heavy smoking. Clin. Pharmacol. Ther.,76:178–184.
[276] Mendelsohn, M.J. 2001. Monoamine Oxidase Inhibitors. In: Clinical. Toxicology., pp. 546–557. Ford, M.D., et al. (Eds.), W.B. Saunders, Philadelphia.
[277] Hodgson, J.M., Chan, S.Y., Puddey, I.B et al. 2004. Phenolic acid metabolites as biomarkers for tea-and coffee-derived polyphenol exposure in human subjects. Br. J. Nutr., 91:301–306.
[278] Klebanoff, M.A., Levine, R.J., Dersimonian, R. et al. 1998. Serum caffeine and paraxanthine as markers for reported caffeine intake in pregnancy. Ann. Epidemiol., 8:107–111.
[279] Rechner, A.R., Spencer, J.P., and Kuhnle, G. 2001. Novel biomarkers of the metabolism of caffeic acid derivatives in vivo. Free Radic. Biol Med., 30:1213–1222.
[280] Nowell, S.A., Ahn, J., and Ambrosone, C.B. 2004. Gene-nutrient interactions in cancer etiology. Nutr. Rev., 62:427–438.
[281] Daly, A.K. 2003. Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam. Clin. Pharmacol., 17:27–41.
[282] Nakajima, M., Yokoi, T., Mizutani, M. et al. 1999. Genetic polymorphism in the 5_-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J. Biochem. (Tokyo)., 125:803– 808.
[283] Sachse, C., Brockmoller, J., Bauer, S., and Roots, I. 1999. Functional significance of a C-? A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br. J. Clin. Pharmacol., 47:445– 449.
[284] Sata, F., Yamada, H., Suzuki, K. et al. 2005. Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol. Hum. Reprod., 11:357–360.
[285] Ariyoshi, N., Miyamoto, M., Umetsu, Y. et al. 2002. Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. Cancer. Epidemiol. Biomarkers. Prev., 11:890–894.
[286] Sweeney, C., Coles, B.F., Nowell, S. et al. 2002. Novel markers of susceptibility to carcinogens in diet: associations with colorectal cancer. Toxicology., 181–182:83–87.
[287] Hein, D.W. 2002. Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat Res., 506–507:65–77.
[288] Manach, C., Scalbert, A., Morand, C. et al. 2004. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr., 79:727–747.
[289] Miners, J.O., McKinnon, R.A., and Mackenzie, P.I. 2002. Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology., 181–182:453–456.