Coffee Abstracts 3



High CYP2A6 enzyme activity as measured by a caffeine test and unique distribution of CYP2A6 variant alleles in Ethiopian population.
            (Aklillu et al., 2014)  Download
CYP2A6 metabolizes clinically relevant drugs, including antiretroviral and antimalarial drugs of major public health importance for the African populations. CYP2A6 genotype-phenotype relationship in African populations, and implications of geographic differences on enzyme activity, remain to be investigated. We evaluated the influence of CYP2A6 genotype, geographical differences, gender, and cigarette smoking on enzyme activity, using caffeine as a probe in 100 healthy unrelated Ethiopians living in Ethiopia, and 72 living in Sweden. CYP2A6 phenotype was estimated by urinary 1,7-dimethyluric acid (17U)/1,7-dimethylxanthine or paraxanthine (17X) ratio. The frequencies of CYP2A6*1B, *1D, *2, *4, *9, and *1x2 in Ethiopians were 31.3, 29.4, 0.6, 0.6, 2.8, and 0.3%, respectively. The overall mean±SD for log 17U/17X was 0.12±0.24 and coefficient of variation 199%. No significant difference in the mean log 17U/17X ratio between Ethiopians living in Sweden versus Ethiopia was observed. Analysis of variance revealed CYP2A6 genotype (p=0.04, F=2.01) but not geographical differences, sex, or cigarette smoking as predictors of CYP2A6 activity. Importantly, the median (interquartile range) of 17U/17X ratio in Ethiopians 1.35 (0.99 to 1.84) was 3- and 11-fold higher than the previously reported value in Swedes 0.52 (0.27 to 1.00) and Koreans 0.13 (0.0 to 0.35), respectively (Djordjevic et al., 2013). Taken together, we report here the relevance of CYP2A6 genotype for enzyme activity in this Ethiopian sample, as well as high CYP2A6 activity and unique distribution of the CYP2A6 variant alleles in Ethiopians as compared other populations described hitherto. Because Omics biomarker research is rapidly accelerating in Africa, CYP2A6 pharmacogenetics and clinical pharmacology observations reported herein for the Ethiopian populations have clinical and biological importance to plan for future rational therapeutics efforts in the African continent as well as therapeutics as a global science.


Coffee and cancer risk: a summary overview.
            (Alicandro et al., 2017) Download
We reviewed available evidence on coffee drinking and the risk of all cancers and selected cancers updated to May 2016. Coffee consumption is not associated with overall cancer risk. A meta-analysis reported a pooled relative risk (RR) for an increment of 1 cup of coffee/day of 1.00 [95% confidence interval (CI): 0.99-1.01] for all cancers. Coffee drinking is associated with a reduced risk of liver cancer. A meta-analysis of cohort studies found an RR for an increment of consumption of 1 cup/day of 0.85 (95% CI: 0.81-0.90) for liver cancer and a favorable effect on liver enzymes and cirrhosis. Another meta-analysis showed an inverse relation for endometrial cancer risk, with an RR of 0.92 (95% CI: 0.88-0.96) for an increment of 1 cup/day. A possible decreased risk was found in some studies for oral/pharyngeal cancer and for advanced prostate cancer. Although data are mixed, overall, there seems to be some favorable effect of coffee drinking on colorectal cancer in case-control studies, in the absence of a consistent relation in cohort studies. For bladder cancer, the results are not consistent; however, any possible direct association is not dose and duration related, and might depend on a residual confounding effect of smoking. A few studies suggest an increased risk of childhood leukemia after maternal coffee drinking during pregnancy, but data are limited and inconsistent. Although the results of studies are mixed, the overall evidence suggests no association of coffee intake with cancers of the stomach, pancreas, lung, breast, ovary, and prostate overall. Data are limited, with RR close to unity for other neoplasms, including those of the esophagus, small intestine, gallbladder and biliary tract, skin, kidney, brain, thyroid, as well as for soft tissue sarcoma and lymphohematopoietic cancer.

In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios.
            (Begas et al., 2007)  Download
A RP-HPLC method was developed for the assessment of caffeine and its metabolites in urine and was used for the evaluation of the CYP1A2, CYP2A6, xanthine oxidase (XO) and N-acetyl-transferase-2 (NAT-2) in vivo activities in 44 Greek volunteers (21 men, 23 women). Spot urine samples were analyzed 6 h after 200 mg caffeine consumption, following a 30 h methylxantine-free diet. The major urinary caffeine metabolites are 1-methyluric acid (1U), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2, CYP2A6, XO and NAT-2 activities were estimated from the metabolic ratios (AFMU + 1U + 1X)/17U, 17U/17X, 1U/(1X + 1U) and AFMU/(AFMU + 1U + 1X), respectively. Metabolites and internal standard were extracted with chloroform/isopropanol (85:15, v/v) and separated on a C18 column by an isocratic HPLC system using a two-step elution with manual switch from solvent A (0.1% acetic acid-methanol-acetonitrile, 92:4:5 v/v) to solvent B (0.1% acetic acid-methanol, 60:40, v/v), and detected at 280 nm. The method exhibited adequate metabolite separation (resolution factors >1.48), accuracy (94.1-106.3%) and intraday and interday precision <8.02 and <8.78%, respectively (n = 6). Smoking affected only CYP1A2, whereas gender had no effect in any enzyme activity. NAT-2 exhibited bimodal distribution, 63.6% of volunteers being slow acetylators. The developed RP-HPLC method was fully validated and successfully applied for the evaluation of CYP1A2, CYP2A6, XO and NAT-2 activities.

Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.
            (Fujimaki et al., 2018)  Download
OBJECTIVE:  To investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography-mass spectrometry. METHODS:  Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography-mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing. RESULTS:  Serum levels of caffeine and 9 of its downstream metabolites were significantly decreased even in patients with early PD, unrelated to total caffeine intake or disease severity. No significant genetic variations in  CONCLUSION:  Absolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies. CLASSIFICATION OF EVIDENCE:  This study provides Class III evidence that decreased serum levels of caffeine and its metabolites identify patients with PD.

Coffee consumption and disease correlations.
            (Gökcen and Şanlier, 2017)  Download
Coffee is one of the most widely consumed beverages in the world. It has primarily consumed due to its stimulant effect and unique taste since the ancient times. Afterwards, its consumption has been historically associated with a lower risk of some diseases such as type 2 diabetes mellitus, obesity, cardiovascular disease and some type of cancer and thus it has also consumed due to health benefits. It contains many bioactive compounds such as caffeine, chlorogenic acids and diterpenoid alcohols which have so far been associated with many potential health benefits. For example, caffeine reduces risk of developing neurodegenerative disease and chlorogenic acids (CGA) and diterpene alcohols have many health benefits such as antioxidant and chemo-preventive. Coffee also have harmful effects. For example, diterpenoid alcohols increases serum homocysteine and cholesterol levels and thus it has adverse effects on cardiovascular system. Overall, the study that supports the health benefits of coffee is increasing. But, it is thought-provoking that the association with health benefits of coffee consumption and frequency at different levels in each study. For this reason, we aimed to examine the health effect of the coffee and how much consumption is to investigate whether it meets the claimed health benefits.

The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: a randomized trial.
            (Grubben et al., 2000)  Download
BACKGROUND:  Epidemiologic studies suggest that coffee use might protect against colorectal cancer. Inconsistencies as to the effect of coffee use and colorectal cancer between epidemiologic studies might be related to the type of coffee brew. OBJECTIVE:  We studied the effect of unfiltered coffee consumption on putative biomarkers for colonic cancer risk. DESIGN:  A total of 64 healthy volunteers (31 men and 33 women), with a mean age of 43 +/- 11 years were randomly assigned to two groups in a crossover design, with two intervention periods of 2 weeks separated by a washout period of 8 weeks. Treatments were 1 L of cafetière (French press) coffee daily or no coffee. At the end of each intervention period, fasting blood samples, colorectal biopsies and 48 h faeces were collected. RESULTS:  No effect of coffee on colorectal cell proliferation, assayed by estimating the Proliferating Cell Nuclear Antigen labelling index, was seen. Additionally, no effects were seen on the concentrations of faecal soluble bile acids and colorectal mucosal glutathione S-transferase activity. However, unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Other aminothiols in plasma also increased on coffee. CONCLUSION:  Unfiltered coffee does not influence the colorectal mucosal proliferation rate, but might increase the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration. Whether this effect indeed contributes to a lower colon cancer risk remains to be established.

Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat.
            (Kot and Daniel, 2008)  Download
The current knowledge on the involvement of cytochrome P450 (P450, CYP) isoforms in the metabolism of caffeine in rat and human liver is reviewed. Attention is also paid to species- and concentration-dependent metabolism of caffeine. Finally, we discuss the P450-mediated metabolism of caffeine in relation to coffee addiction and drug interactions. Due to its safety, favorable pharmacokinetic properties, and P450 isoform-selective metabolism, caffeine has great potential as a metabolic marker substance in both humans and rats, and as a more universal metabolic tool in the latter species. However, the qualitative and relative quantitative contribution of P450 isoforms to the metabolism of caffeine is species- and concentration-dependent. While 3-N-demethylation is quantitatively the main oxidation pathway in human, 8-hydroxylation is the dominant metabolic pathway in rat. Both of these main reactions in the two species are specifically catalyzed by CYP1A2. Caffeine may be applied as a marker substance for assessing the activity of CYP1A2 in human and rat liver, but by using different reactions: 3-N-demethylation in humans and C-8-hydroxylation in rats. In addition, caffeine can be used to preliminarily and simultaneously estimate CYP2C activity in rat liver using 7-N-demethylation as a marker reaction. On the other hand, CYP3A4-catalyzed 8-hydroxylation in humans is not sufficiently isoform-specific to mark the activity of CYP3A4. Caffeine pharmacokinetics may be changed by drugs affecting the activity of CYP1A2 (human and rat) or CYP2C (rat), e.g. via autoinduction or by treatment with certain antidepressants or neuroleptics. Therefore, patients taking caffeine-containing medicine or coffee drinkers taking drugs that interact with CYP1A2 may require proper dosage adjustments upon caffeine ingestion and cessation.

Coffee and liver health.
            (Morisco et al., 2014)  Download
Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases. Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma. The mechanisms of action through which it exerts its beneficial effects are not fully understood. Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver and promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to "treat" patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients.

The Impact of Coffee on Health.
            (Nieber, 2017)  Download
Coffee is one of the most popular and widely consumed beverages worldwide due to its stimulating effects on the central nervous system as well as its taste and aroma. Coffee is a complex mixture of more than 800 volatile compounds whereas caffeine and chlorogenic acids are the most common compounds. During the last years, coffee has progressively moved to a less negative position on health due to its better-known pharmacology. Caffeine, e.g., in a cup of coffee, appears to exert most of its effects through an antagonism of the adenosine receptors. Novel approaches in epidemiological studies and experimental researches suggest that coffee consumption may help to prevent several chronic diseases, including type 2 diabetes mellitus and liver disease. Most prospective cohort studies have not found coffee consumption to be associated with a significantly increased cardiovascular disease risk. There is also evidence that decaffeinated coffee may, in some respect, have similar benefits as regular coffee, indicating that besides caffeine other components contribute to the health protecting effects. 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. This review provides up-to-date information about coffee on health. Topics addressed include the cardiovascular system, liver diseases, and diabetes as well as gastrointestinal disorders.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.
            (Popat et al., 2011)  Download
BACKGROUND AND PURPOSE:  In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS:  Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS:  Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION:  In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.


Association between coffee consumption and all-sites cancer incidence and mortality.
            (Sado et al., 2017)  Download
The preventive effect of coffee on cancer at different sites has been reported, but the effect on all-sites cancer incidence has not been extensively investigated. We evaluated the association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality among 39 685 men and 43 124 women (age 40-79 years, at baseline), in the Three-Prefecture Cohort Study. The association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality was assessed by a Cox proportional hazards regression model, adjusted for potential confounders. During 411 341 person-years among men and 472 433 person-years among women, a total of 4244 men and 2601 women developed cancer at different sites and a total of 3021 men and 1635 women died of cancer at different sites. We showed an inverse association between frequency of coffee consumption and all-sites cancer incidence in both men and women. Comparing participants who consumed coffee with those who never drank coffee, the adjusted hazard ratios (95% confidential interval) for all-sites cancer incidence was 0.74 (0.62-0.88) for coffee consumption of ≥5 cups/day in men (P for trend < 0.001) and 0.76 (0.58-1.02) in women (P for trend = 0.020). Coffee consumption frequency was inversely associated with mortality from all-sites cancer. In this population, increasing coffee consumption resulted in a decreased risk of all-sites cancer incidence and mortality.

Beneficial Role of Coffee and Caffeine in Neurodegenerative Diseases: A Minireview.
            (Sc and Muralidhara, 2016)  Download
Coffee is among the most widespread and healthiest beverages in the world. Coffee typically contains more caffeine than most other beverages, and is widely and frequently consumed. Thus, it contributes significantly to the overall caffeine consumption within the general population, particularly in adults. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health-promoting potential. Several lines of evidence have highlighted the beneficial effects towards several disease conditions including Type II diabetes, hepatitis C virus, hepatocellular carcinoma, nonalcoholic fatty liver disease and neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The health-promoting properties of coffee are largely attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, and hydroxy hydroquinone. In this minireview, an attempt has been made to discuss the various evidences which are mainly derived from animal and cell models. Various mechanisms chiefly responsible for the beneficial effects of caffeine have also been briefly outlined. A short note on the undesirable effects of excessive coffee intakes is also presented.


PharmGKB summary:  caffeine pathway.
            (Thorn et al., 2012)  Download

Coffee and cancer risk: A meta-analysis of prospective observational studies.
            (Wang et al., 2016) Download
Meta-analyses on coffee and cancer incidence mainly restricted to limited cancers. We carried out a more comprehensive meta-analysis of cohort studies to explore association between coffee and most cancer types. We conducted comprehensive search and summarized relative risk (RR) and 95% confidence intervals for the highest versus lowest coffee intake and cancer using STATA12. We conducted dose-analysis if result suggested significant association. The publication bias was evaluated with begg's and egger's test. Finally, 105 individual prospective studies were included. Inverse associations were observed on oral, pharyngeal, colon, liver, prostate, endometrial cancer and melanoma, with RR 0.69 (95% CI = 0.48-0.99, I

Can coffee consumption lower the risk of Alzheimer's disease and Parkinson's disease? A literature review.
            (Wierzejska, 2017)  Download
In light of the fact that the number of elderly citizens in society is steadily increasing, the search for dietary factors which might prolong mental agility is growing in significance. Coffee, together with its main ingredient, caffeine, has been the focus of much attention from various researchers, as data on its beneficial effects on human health continue to accumulate. Most reports indicate that moderate coffee consumption may in fact lower the risk for common neurodegenerative conditions, i.e. Alzheimer's and Parkinson's diseases. Regardless, due to their complex pathogenesis as well as methodology of scientific research, the exact impact of coffee consumption remains to be fully elucidated. At present, it seems safe to inform the general public that coffee drinkers need not fear for their health. Possibly, in the future experts will recommend drinking coffee not only to satisfy individual taste preferences but also to decrease age-related mental deterioration.



Aklillu, E, et al. (2014), ‘High CYP2A6 enzyme activity as measured by a caffeine test and unique distribution of CYP2A6 variant alleles in Ethiopian population.’, OMICS, 18 (7), 446-53. PubMed: 24380444
Alicandro, G, A Tavani, and C La Vecchia (2017), ‘Coffee and cancer risk: a summary overview.’, Eur J Cancer Prev, 26 (5), 424-32. PubMed: 28288025
Begas, E, et al. (2007), ‘In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios.’, Biomed Chromatogr, 21 (2), 190-200. PubMed: 17221922
Fujimaki, M, et al. (2018), ‘Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.’, Neurology, 90 (5), e404-11. PubMed: 29298852
Gökcen, BB and N Şanlier (2017), ‘Coffee consumption and disease correlations.’, Crit Rev Food Sci Nutr, 1-13. PubMed: 28853910
Grubben, MJ, 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 (9), 1181-90. PubMed: 10971235
Kot, M and WA Daniel (2008), ‘Caffeine as a marker substrate for testing cytochrome P450 activity in human and rat.’, Pharmacol Rep, 60 (6), 789-97. PubMed: 19211970
Morisco, F, et al. (2014), ‘Coffee and liver health.’, J Clin Gastroenterol, 48 Suppl 1 S87-90. PubMed: 25291138
Nieber, K (2017), ‘The Impact of Coffee on Health.’, Planta Med, 83 (16), 1256-63. PubMed: 28675917
Popat, RA, et al. (2011), ‘Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson’s disease.’, Eur J Neurol, 18 (5), 756-65. PubMed: 21281405
Sado, J, et al. (2017), ‘Association between coffee consumption and all-sites cancer incidence and mortality.’, Cancer Sci, 108 (10), 2079-87. PubMed: 28746796
Sc, Y and Muralidhara (2016), ‘Beneficial Role of Coffee and Caffeine in Neurodegenerative Diseases: A Minireview.’, AIMS Public Health, 3 (2), 407-22. PubMed: 29546172
Thorn, CF, et al. (2012), ‘PharmGKB summary: caffeine pathway.’, Pharmacogenet Genomics, 22 (5), 389-95. PubMed: 22293536
Wang, A, et al. (2016), ‘Coffee and cancer risk: A meta-analysis of prospective observational studies.’, Sci Rep, 6 33711. PubMed: 27665923
Wierzejska, R (2017), ‘Can coffee consumption lower the risk of Alzheimer’s disease and Parkinson’s disease? A literature review.’, Arch Med Sci, 13 (3), 507-14. PubMed: 28507563