Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocyclic amines. We aimed to clarify the existe nce of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenoty ping, The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caf feine (17U + 17X/137X) ratio and log-transformed data were determined, Prob it plots were constructed and the distribution fitted using maximum likelih ood method. The CYP1A2 gene, including upstream regulatory regions, was exa mined for sequence polymorphisms using the single-strand conformation polym orphism technique in 19 individuals and by complete DNA sequencing in two i ndividuals from the extremes of the distribution, We found a similar range (1.45-18.65) and median (6.7) for the 17U + 17X/137X ratio to that found in previous studies of non-smoking Caucasians and no effect of sex, The 17U 17X/137X ratio gave a normal distribution when log-transformed, Maximum li kelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it h as fewer parameters, There was no evidence for significant DNA sequence dif ferences between fast and slow metabolizers, although some differences from published sequences including a silent polymorphism in exon 7 which were u nlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that th e wide interindividual variation in activity may be due to environmental fa ctors. Pharmacogenetics 9:367-375 (C) 1999 Lippincott Williams & Wilkins.