Enhanced expression of rat hepatic microsomal epoxide hydrolase by methylthiazole in conjunction with liver injury

Microsomal epoxide hydrolase (mEH) is inducible by a number of xenobiotics. Induction of mEH by certain chemopreventive agents may implicate the prote ctive effect. In contrast, many of carcinogenic agents also induce the enzy me. The hepatotoxicity and mEH expression by methylthiazoles, which are inc orporated as functional groups in a number of therapeutic agents, were asse ssed in the rat liver to study the structural basis for the enzyme inductio n and the correlative enzyme expression with hepatotoxicity. Among the meth ylthiazoles examined, 4-methylthiazole (MT) at the daily dose of 1.17 mmol/ kg body weight caused hepatic necrosis and degeneration after 1-3 consecuti ve daily treatment(s), whereas 4,5-dimethylthiazole (DT) and 2,4,5-trimethy lthiazole (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 affect ed mEH expression. The mRNA increase was consistent with the protein induct ion. Hence, the methylthiazole causing hepatotoxicity was more active in in ducing the enzyme. Whereas treatment with MT at the dose of 0.35 mmol/kg ca used no hepatotoxicity, MT caused hepatic necrosis in starving rats. Northe rn blot analysis showed that the mEH mRNA level was increased to a greater extent by MT in starving rats than in control animals. Conversely, treatmen t 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 res ults demonstrated that the methylthiazole which caused hepatotoxicity also up-regulated mEH. expression, whereas other methylthiazoles showing no toxi city minimally increased the gene expression. The observation that the exte nt of mEH expression by MT was highly associated with that of liver injury raised the notion that mEH expression by xenobiotics may not necessarily re present the beneficial and protective effects. (C) 2000 Elsevier Science Ir eland Ltd. All rights reserved.