Protein expression of the hepatic
CYP2E1 has been reported to be increased in diabetic rats. This
enzyme is the primary metabolizer of
chlorzoxazone (CZX) to
6-hydroxychlorzoxazone (
OH-CZX). Although patients with
liver cirrhosis have a higher prevalence of
diabetes mellitus, there have been no reported studies on the
protein expression of
CYP2E1 in rats induced to have
liver cirrhosis and
diabetes mellitus by injection of N-
dimethylnitrosamine followed by
streptozotocin [
liver cirrhosis with
diabetes mellitus (LCD) rats]. Thus, in the present study, the pharmacokinetics of CZX and
OH-CZX were evaluated in LCD rats. Compared with control rats, LCD rats had significantly decreased (by 62%) total liver
protein and significantly increased (by 124%)
protein expression of
CYP2E1, but the intrinsic clearance (Cl(int); formation of
OH-CZX per milligram
protein) was comparable in both groups of rats. As a result, the relative Cl(int) was also comparable for the two groups. Thus,
OH-CZX formation in LCD and control rats was expected to be similar. As expected, after i.v. (20 mg/kg) and p.o. (50 mg/kg) administration of CZX, the area under the curve (AUC) of
OH-CZX was comparable in control and LCD rats (i.v., 571 +/- 85.8 and 578 +/- 413 microg x min/ml, respectively; p.o., 1540 +/- 338 and 2170 +/- 1070 microg x min/ml, respectively). In LCD rats, the AUC(
OH-CZX)/AUC(CZX) ratio was similar to the value in control rats after i.v. and p.o. administration. These results indicate that
OH-CZX can be used as a chemical probe to assess the activity of
CYP2E1 in LCD rats.