EXPRESSION OF CYTOCHROME P4502E1 IN HUMAN LIVER - ASSESSMENT BY MESSENGER-RNA, GENOTYPE AND PHENOTYPE

Cytochrome P4502E1 (CYP2E1) is constitutively expressed in human liver and is responsible for the metabolic bioactivation of a wide variety of xenobiotics, including a number of protoxins and procarcinogens. CY P2E1 expression is regulated at several levels including pre-transcrip tional, transcriptional and post-transcriptional levels, and any varia tion in enzyme concentration and hence activity may represent increase d risk of toxicity or carcinogenicity, We have investigated variabilit y in the levels of CYP2E1 mRNA, protein and functional activity in a h uman liver bank, and attempted to relate these parameters to the RsaI restriction fragment length polymorphism in the 5'-flanking region, Va riation in CYP2E1 mRNA (18-fold) was greater than the variation seen i n CYP2E1 protein (twofold) and functional activity (fourfold) determin ed using two probe substrates, chlorzoxazone and p-nitrophenol, Althou gh protein and functional activity showed a significant correlation (r = 0.93 and r = 0.83 for chlorzoxazone and p-nitrophenol, respectively ), there was no correlation between ally of these parameters and mRNA levels, Also, the variation in CYP2E1 activity could not be directly a ccounted for by the RsaI polymorphism in our samples. In conclusion ou r results are consistent with a complex regulation of CYP2E1 and the f act that it is highly conserved in the human population, The absence o f a relationship between the RsaI polymorphism and CYP2E1 activity is consistent with other studies performed in Caucasians, but does not ex clude an effect of this polymorphism on inducibility of CYP2E1. Pharma cogenetics 8:411-421 (C) 1998 Lippincott Williams & Wilkins.