Kim R B, Yamazaki H, Chiba K, O'Shea D, Mimura M, Guengerich F P, Ishizaki T, Shimada T, Wilkinson G R
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
J Pharmacol Exp Ther. 1996 Oct;279(1):4-11.
Chlorzoxazone's disposition after oral administration was determined in 20 young healthy Caucasian men and a similar group of Japanese men. The drug's plasma concentrations were significantly higher and its rate of elimination slower in Japanese compared to Caucasian men. Accordingly, chlorzoxazone's oral clearance was smaller (40%) in Japanese men and a similar difference (30%) was still apparent after normalizing for body weight (3.74 +/- 1.23 versus 5.05 +/- 1.41 ml.min-1.kg-1, P < .05). This slower elimination was associated with a reduced (fractional) clearance by 6-hydroxylation (2.34 +/- 1.04 ml.min-1.kg-1 versus 3.23 +/- 1.10, P < .05). Because such metabolism is mediated by cytochrome P4502E1 (CYP2E1), these findings suggest a lower level of the enzyme's catalytic activity in Japanese men. This was confirmed by in vitro studies with microsomes prepared from livers of individuals representative of the two racial groups. CYP2E1 levels were lower (61% P < .002) and CYP2E1-mediated chlorzoxazone 6-hydroxylase (22%, P < .001) and aniline 4-hydroylase (35%, P < .0001) activities were reduced in Japanese preparations compared to those from Caucasians. No relationships were found between measures of CYP2E1 activity, both in vivo and in vitro, and genomic polymorphisms in the CYP2E1 gene identified by Rsal/Pstl and Dral restriction fragment length polymorphisms. Collectively, these data show an interracial difference in CYP2E1 activity. Because this enzyme is importantly involved in the activation of environmental procarcinogens, such a difference may account, in part, for the lower rate of some cancers, e.g., lung cancer, in Japanese compared to Caucasians men.
