Genetic and dietary predictors of CYP2E1 activity: A phenotyping study in Hawaii Japanese using chlorzoxazone

Cytochrome P4502E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low mole cular weight organic compounds. An RsaI polymorphism is present in the 5'-f lanking region of the CYP2E1 gene, which could possibly affect its transcri ption, However, the relationship between genotype and the phenotypic cataly tic activity of the enzyme has not been defined. Also, the effects in human s of specific dietary factors, other than ethanol, which have been shown in animal and in vitro studies to modulate CYP2E1 activity, are unknown. Acco rdingly, the CYP2E1-mediated metabolism of chlorzoxazone to its 6-hydroxy m etabolite was investigated in 50 healthy Japanese of both sexes in Hawaii. The oral clearance of the in vivo probe, the trait measure of CYP2E1 activi ty, was smaller than that reported in European-Americans. Significantly, af ter adjustment for age and sex, the oral clearance of chlorzoxazone decreas ed with the number of variant c2 alleles, and its mean in the c2/c2 genotyp e (147 ml/min) was statistically lower (P less than or equal to 0.05) than that for either the homozygous wild-type (238 ml/min) or the heterozygote ( 201 ml/min) genotypes, Stepwise multiple regression analysis indicated that body weight was a major contributor to the interindividual variability in the oral clearance of chlorzoxazone, accounting for 43% of the variance. Co nsumption of lettuce, broccoli, and black tea explained additional componen ts of the variability (7, 5, and 6%, respectively), as did medication use ( 3%), age (4%), and CYP2E1 genotype (5%), Overall, 73% of the variance could be accounted for by these variables. Body weight, lettuce, and use of medi cations were associated with increased CYP2E1 activity, and the other covar iates were associated with reduced enzyme function, Because of the role tha t CYP2E1 plays in procarcinogen activation, especially of N-nitrosamines in volved in lung cancer, the identified factors may account in part for obser ved differences in individual susceptibility to disease and may also have i mplications for cancer prevention.