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 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.
Cho
M K
MK
College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul, South Korea.
Kim
S G
SG
D000818:Animals; D015152:Blotting, Northern; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D003545:Cysteine / Q000494:pharmacology; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D008297:Male; D008715:Methionine / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D009336:Necrosis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*
D013844:Thiazoles; D012313:RNA; D008715:Methionine; D004851:Epoxide Hydrolases; D003545:Cysteine; C410590:4-methylthiazole