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 molecular weight organic compounds. An RsaI polymorphism is present in the 5'-flanking region of the CYP2E1 gene, which could possibly affect its transcription. However, the relationship between genotype and the phenotypic catalytic activity of the enzyme has not been defined. Also, the effects in humans of specific dietary factors, other than ethanol, which have been shown in animal and in vitro studies to modulate CYP2E1 activity, are unknown. Accordingly, the CYP2E1-mediated metabolism of chlorzoxazone to its 6-hydroxy metabolite was investigated in 50 healthy Japanese of both sexes in Hawaii. The oral clearance of the in vivo probe, the trait measure of CYP2E1 activity, was smaller than that reported in European-Americans. Significantly, after adjustment for age and sex, the oral clearance of chlorzoxazone decreased with the number of variant c2 alleles, and its mean in the c2/c2 genotype (147 ml/min) was statistically lower (P < or = 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. Consumption of lettuce, broccoli, and black tea explained additional components 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 medications were associated with increased CYP2E1 activity, and the other covariates were associated with reduced enzyme function. Because of the role that CYP2E1 plays in procarcinogen activation, especially of N-nitrosamines involved in lung cancer, the identified factors may account in part for observed differences in individual susceptibility to disease and may also have implications for cancer prevention.
Marchand
L L
LL
Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813, USA.
Wilkinson
G R
GR
Wilkens
L R
LR
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001213:Asian / Q000235:genetics*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D004032:Diet / Q000009:adverse effects*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006254:Hawaii; D006801:Humans; D008658:Inactivation, Metabolic; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D012044:Regression Analysis
D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone