Biochemistry and molecular biology of the human CYP2C subfamily

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Abstract

The cytochromes P450 (CYP) are a superfamily of hemoproteins which metabolize foreign chemicals as well as a number of endogenous compounds such as steroids. The human CYP 2C subfamily appears to principally metabolize a number of clinically used drugs. Four members of this subfamily have been identified in humans: CYP 2C8, CYP 2C9. CYP 2C18, and CYP 2C19. CYP 2C9 is important in the metabolism certain of therapeutically used drugs including the anticoagulant drug warfarin and a number of nonsteroidal antiinflammatory drugs. A number of allelic variants of CYP 2C9 exist in humans, but the effects of these allelic variants on metabolism in vivo remain to be determined. A well-characterized genetic polymorphism occurs in the 2C subfamily which is associated with the metabolism of the anticonvulsant drug mephenytoin. In population studies, individuals can be segregated into extensive and poor metabolizers of mephenytoin. Poor metabolizers are unable to 4'-hydroxylate the S-enantiomer of mephenytoin. There are marked interracial variations in the frequency of the poor metabolizer phenotype which represents 3–5% of Caucasians, but 18–23% of Oriental populations. The mechanism of this polymorphism has been recently elucidated. The enzyme responsible for S-mephenytoin metabolism has been shown to be CYP2C19, and two defects in the CYP 2C19 gene have been described in poor metabolizers. The first defect, CYP 2C19m1, consists of the creation of an aberrant splice site in exon 5. This defect accounts for 75–85% of Caucasian and Japanese poor metabolizers. A second defect, CYP 2C 19m2, has been found only in Oriental populations and accounts for the remaining 25% of poor metabolizers in Japanese populations. The availability of genotyping tests for this polymorphism will enhance the assessment of the role of this pathway in clinical studies.

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