DIFFERENT REGULATION AND EXPRESSION OF THE HUMAN CYP2E1 GENE DUE TO THE RSAI POLYMORPHISM IN THE 5'-FLANKING REGION

The effects of two genetically associated polymorphisms [c1 allele: Ps tI -, RsaI +; c2 allele: PstI +, RsaI -] in the 5'-flanking region on the regulation and expression of the human CYP2E1 gene were investigat ed. DNase I footprinting and CAT activity analyses using various delet ion mutants constructed with DNA segments from genotype A (c1/c1) or C (c2/c2) and SV40 or an endogenous promoter showed that the RsaI polym orphism affects the binding of a transcription factor and the transcri ptional activation of CYP2E1, while the PstI polymorphism has little e ffect. The correlation between the genotypes and expression levels of CYP2E1 mRNA were examined in peripheral lymphocytes of 86 individuals by RT-PCR, the alcohol consumption by the subjects being taken into ac count. In non-drinkers, the mean ratio of the expression of CYP2E1 mRN A to that of GAPDH mRNA in genotype B (c1/c2) was 1.7-fold higher than that in genotype A (0.05<p<0.10). As compared to non-drinkers with ge notype A, subjects with genotype B who drank alcohol on a daily basis expressed about 2.0-fold higher levels of CYP2E1 mRNA (p<0.01). These results indicate that a RsaI polymorphism in the 5'-flanking region of CYP2E1 may lead to inter-individual differences in CYP2E1-mediated mi crosomal drug oxidation activities, including oxidation of N-nitrosami nes.