Interindividual variability of chlorzoxazone 6-hydroxylation in men and women and its relationship to CYP2E1 genetic polymorphisms.
Chlorzoxazone 6-hydroxylation is mediated by CYP2E1, and its measurement provides an in vivo probe of the enzyme's activity. To determine the population distribution of such activity, the disposition of chlorzoxazone and its 6-hydroxy metabolite was determined after oral administration to 70 white subjects (40 men and 30 women) residing in middle Tennessee. Both oral (330 +/- 111 ml.min-1, mean +/- SD) and fractional (213 +/- 86 ml.min-1) clearances varied fourfold to fivefold within the population and were unimodally distributed in a visually normal fashion. Clearance values were one-third greater in men than in women, but such differences were less striking after normalization according to body weight. Attempts to develop a single-time-point measure of 6-hydroxylating ability on the basis of plasma levels or urinary excretion of chlorzoxazone or its metabolite were unsuccessful. Genetic polymorphisms (Pst I and Rsa I restriction fragment length polymorphisms) in the 5'-flanking region of CYP2E1 deoxyribonucleic acid obtained from peripheral leukocytes were not associated with differences in the disposition of chlorzoxazone. Similarly, no major effects on 6-hydroxylation were associated with mutations in intron 6 associated with a Dra I restriction fragment length polymorphism. The interindividual variability in CYP2E1 activity as measured in vivo in healthy subjects appears to be considerably less than that expected based on in vitro studies. Whether such variability is associated with individual susceptibility to CYP2E1-mediated toxicity remains to be determined.
Kim
R B
RB
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6600, USA.
O'Shea
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D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002753:Chlorzoxazone / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D012727:Sex Characteristics
D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone