Importance of pharmacogenetic and environmental factors for variation in caffeine disposition: with special emphasis on CYP1A2, CYP2A6, NAT2 and XO

摘要: Inter-individual variation in response to drugs conveys considerable risk of either therapy failure or drug toxicity. Caffeine, as one the most frequently used psychoactive substances world, is not an exception, and both lack effects adverse reactions have been observed after usual doses. In addition inter-individual differences at drug-receptor level drug-drug interactions, variability caffeine metabolism has proposed a possible explanation. The objective this study was investigate influence pharmacogenetic environmental factors, which are known be importance for disposition, on activity enzymes involved metabolism, namely cytochrome P450 1A2 (CYP1A2) 2A6 (CYP2A6), N-acetyltransferase-2 (NAT2) xanthine oxidase (XO). unrelated healthy volunteers from three ethnically distinct populations: Serbian (n=140), Swedish (n=190) Korean (n=150). Phenotyping CYP1A2, CYP2A6, NAT2 XO performed using probe measuring concentration parent compound its metabolites plasma urine samples. CYP1A2 estimated by 17X/137X ratio, activities were determined 17U/17X, AFMU/(AFMU+1X+1U) 1U/(1U+1X) urinary ratios, respectively. addition, subjects genotyped important CYP2A6 polymorphisms. Daily consumption least cups coffee non-OC (oral contraceptive) users significantly increased enzyme Swedes (P A inducibility found (P=0.022) (P=0.016) nonsmoking heavy consumers. There no significant difference among genotypes non–heavy Controlling effect smoking, habit OC use, lower ratio Serbs than (P=0.0003). Comparison between Koreans revealed that functional alleles more frequent former, whereas defective latter (P≤0.002). genotype affected populations (P=0.004), while sex, age, cigarette smoking use observed. higher compared Koreans, with 3.16% 18.75% being slow metabolizers (P=0.0001). two remained when controlling effect, i.e. within rapid (P=0.0007) intermediate (P=0.04) groups. Rapid acetylator predominant phenotype Serbs, present 55% population. Significant genotypephenotype association detected polymorphism. Eur J Clin Pharmacol 2010; 66(7):697-703. III. Djordjevic N, Carrillo JA, Ueda Gervasini G, Fukasawa T, Suda A, Jankovic S, Aklillu E. gene polymorphisms Serbs: unprecedented high prevalence acetylators white 2011; 51: 7: 994-1003. IV. Roh HK, Karlsson Bertilsson L, genotype-phenotype Koreans. DOI: 10.1177/0091270011420261 V. van den Broek MPJ, Comparisons manuscript.