Genetic repeat polymorphism in the regulating region of CYP2E1: Frequency and relationship with enzymatic activity in alcoholics

Background: Differences in the regulatory region of the CYP2E1 gene could b e responsible for the interindividual variation in the cytochrome P-450 2E1 (CYP2E1) involved in ethanol oxidation. Recently, a polymorphic repeat seq uence in the human gene was described between -2178 and -1945 base pairs. I ts frequency seemed to vary among different ethnic populations, and it was suspected to be related to an increased inducibility to further ethanol int ake. In the study reported here, the frequency of this polymorphism was inv estigated in a white French population. Its relationship with the previousl y described PstI/ RsaI or DraI CYP2E1 polymorphisms, alcoholism, alcoholic liver disease, and inducibility of CYP2E1 by ethanol was examined. Methods: The polymorphic region was characterized by polymerase chain react ion in 103 controls, 148 alcoholic subjects without liver diseases, and 98 others with liver cirrhosis. By using in vivo chlorzoxazone (CHZ) metabolis m, CYP2E1 phenotype was assessed in 36 non-ethanol-induced subjects (17 con trols and 19 withdrawn alcoholics) and in 14 ethanol-induced subjects (10 c ontrols after ingestion of 0.8 g/kg ethanol and four alcoholics with 100 g of daily intake). This phenotype was expressed as the 6-hydroxy CHZ/CHZ rat io. Results: The rare allele frequency was found to be 1.58% in whites (n = 349 ). Neither significant association with alcoholism or alcoholic liver disea ses, nor relationship with the PstI/RsaI polymorphism, was observed. But th e DraI polymorphism was more frequent among the heterozygous subjects when compared with wild-type homozygous ones (p < 0.05). The CYP2E1 phenotype wa s similar in wild-type homozygotes and in heterozygotes at the constitutive level, as well as after induction with ethanol. Conclusions: Our data suggest that CYP2E1 repeat polymorphism does not seem to constitute a major factor for interindividual differences in CYP2E1 exp ression and susceptibility to alcohol-related disorders in whites.