Microsomal epoxide hydrolase (mEH) is inducible by a number of
xenobiotics. Induction of mEH by certain chemopreventive agents may implicate the protective effect. In contrast, many of carcinogenic agents also induce the
enzyme. The hepatotoxicity and mEH expression by methylthiazoles, which are incorporated as functional groups in a number of therapeutic agents, were assessed in the rat liver to study the structural basis for the enzyme induction and the correlative
enzyme expression with hepatotoxicity. Among the methylthiazoles examined,
4-methylthiazole (MT) at the daily dose of 1.17 mmol/kg
body weight caused hepatic
necrosis and degeneration after 1-3 consecutive daily treatment(s), whereas 4, 5-dimethylthiazole (DT) and
2,4,5-trimethylthiazole (TT) elicited no toxicity. Treatment of rats with MT at the daily dose of 1.17 mmol/kg increased the mEH
mRNA by 17- and 7-fold at day 1 and day 3, respectively, relative to control. Whereas DT caused 5- and 2-fold increases in mEH
mRNA at day 1 and day 3, respectively, TT minimally affected mEH expression. The
mRNA increase was consistent with the
protein induction. Hence, the methylthiazole causing hepatotoxicity was more active in inducing the
enzyme. Whereas treatment with MT at the dose of 0.35 mmol/kg caused no hepatotoxicity, MT caused hepatic
necrosis in starving rats. Northern blot analysis showed that the mEH
mRNA level was increased to a greater extent by MT in starving rats than in control animals. Conversely, treatment of starving rats with either
cysteine or
methionine prior to MT prevented the hepatic
necrosis. Elevation of the mEH
mRNA by MT in starving animals was also inhibited by either
cysteine or
methionine pretreatment. These results demonstrated that the methylthiazole which caused hepatotoxicity also up-regulated mEH expression, whereas other methylthiazoles showing no toxicity minimally increased the gene expression. The observation that the extent of mEH expression by MT was highly associated with that of liver injury raised the notion that mEH expression by
xenobiotics may not necessarily represent the beneficial and protective effects.