CYP2E1 expression in human lymphocytes from various ethnic populations

Background: Monitoring CYP2E1 levels in alcoholic individuals holds inheren t appeal because such determinations might indicate individuals at increase d risk for alcoholic liver disease. We previously demonstrated that lymphoc yte CYP2E1 expression reflects in vivo activity of the hepatic enzyme. Methods: To further validate this approach, the current investigation compa red lymphocyte CYP2E1 content and chlorzoxazone pharmacokinetics in 51 alco holic and nonalcoholic White, Navajo, and Mexican American subjects. After an oral dose of chlorzoxazone, blood samples were collected and lymphocytes isolated. Results: Alcoholics exhibited a 2-fold elevation in lymphocyte CYP2E1 messe nger ribonucleic acid (mRNA) and protein compared to nonalcoholics. Chlorzo xazone clearance rates were 1.9-fold higher and area under the concentratio n curve (AUC) values 1.8-fold lower in alcoholic individuals compared to no nalcoholics. Furthermore, chlorzoxazone clearance rates correlated (I = 0.5 5, p < 0.01, n = 38) with lymphocyte CYP2E1 mRNA content, and transcript le vels further correlated (r = 0.52, p < 0.001, n = 38) with CYP2E1 protein c ontent. To compare phenotype with genotype, restriction fragment length pol ymorphism analyses on deoxyribonucleic acid samples were performed to ident ify polymorphisms in the CYP2E1 gene. No subjects were homozygous for rare alleles c2 or C. Nonetheless, 27% of the Navajos and 15% of the Mexican Ame ricans were heterozygous for the c2 allele. Two White subjects appeared het erozygous (c1/c2) when RsaI was used to characterize CYP2E1 genotype but ho mozygous (c1/c1) at the PstI locus. Fifteen percent of Mexican American sub jects, 20% of Navajo subjects, and 6% of White subjects were heterozygous f or the C allele. Neither CD nor c1/c2 genotypes were associated with alcoho lism. Conclusions: Human lymphocyte CYP2E1 mRNA levels may be useful predictors o f alcohol-mediated alterations in hepatic CYP2E1 activity. Moreover, ethnic ity does not appear to play a major role in the levels of expression of lym phocyte CYP2E1.