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

Lookup NU author(s): Dr Mark Welfare, Emeritus Professor Murray Aitkin, Professor Margaret Bassendine, Professor Ann Daly

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Abstract

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocycle amines. We aimed to clarify the existence of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenotyping. The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caffeine (17U + 17X/137X) ratio and log-transformed data were determined. Probit plots were constructed and the distribution fitted using maximum likelihood method. The CYP1A2 gene, including upstream regulatory regions, was examined for sequence polymorphisms using the single-strand conformation polymorphism technique in 19 individuals and by complete DNA sequencing in two individuals 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 likelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it has fever parameters. There was no evidence for significant DNA sequence differences between fast and slow metabolizers, although some differences from published sequences including a silent polymorhpism in exon 7 which were unlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that the wide interindividual variation in activity may be due to environmental factors.


Publication metadata

Author(s): Aitkin M; Daly AK; Bassendine MF; Welfare MR

Publication type: Article

Publication status: Published

Journal: Pharmacogenetics

Year: 1999

Volume: 9

Issue: 3

Pages: 367-376

Print publication date: 01/06/1999

ISSN (print): 0960-314X

ISSN (electronic):

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1097/00008571-199906000-00012

DOI: 10.1097/00008571-199906000-00012

PubMed id: 10471069


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