CYP2E1 expression in human lymphocytes from various ethnic populations.
BACKGROUND
Monitoring CYP2E1 levels in alcoholic individuals holds inherent appeal because such determinations might indicate individuals at increased risk for alcoholic liver disease. We previously demonstrated that lymphocyte CYP2E1 expression reflects in vivo activity of the hepatic enzyme.


METHODS
To further validate this approach, the current investigation compared lymphocyte CYP2E1 content and chlorzoxazone pharmacokinetics in 51 alcoholic 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 messenger ribonucleic acid (mRNA) and protein compared to nonalcoholics. Chlorzoxazone clearance rates were 1.9-fold higher and area under the concentration curve (AUC) values 1.8-fold lower in alcoholic individuals compared to nonalcoholics. Furthermore, chlorzoxazone clearance rates correlated (r = 0.55, p < 0.01, n = 38) with lymphocyte CYP2E1 mRNA content, and transcript levels further correlated (r = 0.52, p < 0.001, n = 38) with CYP2E1 protein content. To compare phenotype with genotype, restriction fragment length polymorphism analyses on deoxyribonucleic acid samples were performed to identify 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 Americans were heterozygous for the c2 allele. Two White subjects appeared heterozygous (c1/c2) when RsaI was used to characterize CYP2E1 genotype but homozygous (c1/c1) at the PstI locus. Fifteen percent of Mexican American subjects, 20% of Navajo subjects, and 6% of White subjects were heterozygous for the C allele. Neither CD nor cl/c2 genotypes were associated with alcoholism.


CONCLUSIONS
Human lymphocyte CYP2E1 mRNA levels may be useful predictors of alcohol-mediated alterations in hepatic CYP2E1 activity. Moreover, ethnicity does not appear to play a major role in the levels of expression of lymphocyte CYP2E1.
Raucy
J L
JL
Agouron Institute, University of New Mexico School of Medicine, USA. jraucy@ljiem.org
Schultz
E D
ED
Kearins
M C
MC
Arora
S
S
Johnston
D E
DE
Omdahl
J L
JL
Eckmann
L
L
Carpenter
S P
SP
D000328:Adult; D000437:Alcoholism / Q000097:blood* / Q000235:genetics; D000483:Alleles; D002753:Chlorzoxazone / Q000493:pharmacokinetics*; D019392:Cytochrome P-450 CYP2E1 / Q000097:blood* / Q000235:genetics; D005260:Female; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D017058:Mexican Americans / Q000235:genetics; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000097:blood* / Q000235:genetics; D044465:White People / Q000235:genetics
D009125:Muscle Relaxants, Central; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone