HUMAN CYTOCHROME-P450 2E1 (CYP2E1) - FROM GENOTYPE TO PHENOTYPE

CYP2E1 is involved in the activation of various carcinogens, including N-nitrosamines, which are believed to be important in human carcinoge nesis, Humans exhibit wide interindividual variability in levels of CY P2E1 mRNA and protein, which might explain interindividual differences in susceptibility to carcinogens activated by CYP2E1, Such variabilit y could be due either to genetic polymorphisms observed in the CYP2E1 gene (Rsa I in the 5'-flanking region, Dra I in intron 6 and Taq I in intron 7) or to varying inducibility by xenobiotics, The aim of the pr esent study was to establish whether, in a Caucasian population (n = 9 3), there existed a relationship between allelic forms of the CYP2E1 g ene and the phenotype determined in vitro by hepatic ability to 6-hydr oxylate chlorzoxazone. Rates of chlorzoxazone-6-hydroxylation were sig nificantly correlated with levels of immunochemically measured CYP2E1 (p < 0.001), CYP1A2, 2C8, 2C9, 2C18, 2D6, 3A4 and 3A5 did not appear t o be significantly involved in chlorzoxazone metabolism, whereas the p articipation of CYP1A1 could not be excluded, Frequencies of the rare alleles for the three polymorphism sites were 2.2% for Rsa I, 7.5% for Dra I and 8.5% for Taq I. Despite substantial interindividual variati ons in chlorzoxazone hydroxylase activity, no relationship between any of the three polymorphisms and CYP2E1 activity was established, There fore, in humans, interindividual variability in CYP2E1 levels is proba bly due to differing induction levels as a result of environmental fac tors, or to genetic factors other than those studied in this work.