Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione.
Methimazole (MMI) (>0.1 mmol kg(-1), p.o.) given in combination with DL-buthionine sulphoximine (BSO) (3 mmol kg(-1), i.p., 1 h before MMI administration), an inhibitor of glutathione (GSH) synthesis, caused liver injury in mice. The injury was characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase (ALT) activity. Methionazole (2 mmol kg(-1)) alone resulted in only a marginal increase in serum ALT activity, but produced no histopathological changes in the liver. Pretreatment with hepatic cytochrome P-450 monooxygenase inhibitors--cobalt chloride, isosafrole, methoxsalen, metyrapone and piperonyl butoxide-prevented or tended to suppress the hepatotoxicity induced by MMI in combination with BSO. Treatment with N,N-dimethylaniline and ethyl methyl sulphide, competitive substrates of flavin-containing monooxygenases (FMO), also resulted in remarkable suppression of the hepatotoxicity caused by MMI in combination with BSO. These results suggest that MMI is activated by reactions mediated by both cytochrome P-450 monooxygenases and FMO, and that the inadequate rates of detoxification of the resulting metabolite are responsible for the hepatotoxicity in GSH-depleted mice.
Mizutani
T
T
Department of Food Sciences and Nutritional Health, Kyoto Prefectural University, Japan. mizutani@kpu.ac.jp
Murakami
M
M
Shirai
M
M
Tanaka
M
M
Nakanishi
K
K
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D019328:Buthionine Sulfoximine / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008713:Methimazole / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR
D019328:Buthionine Sulfoximine; D008713:Methimazole; D000410:Alanine Transaminase; D005978:Glutathione