Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione
| Autor: | Mihoko Murakami, Mutsuko Shirai, Kazuo Nakanishi, Maki Tanaka, Tamio Mizutani |
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| Rok vydání: | 1999 |
| Předmět: |
Male
medicine.medical_specialty Metabolite Toxicology Mice chemistry.chemical_compound Internal medicine medicine Animals Buthionine sulfoximine Buthionine Sulfoximine Liver injury Mice Inbred ICR Methimazole Dose-Response Relationship Drug biology Chemistry Liver Diseases Centrilobular necrosis Alanine Transaminase Glutathione Monooxygenase medicine.disease Endocrinology Liver Alanine transaminase Isosafrole biology.protein Chemical and Drug Induced Liver Injury |
| Zdroj: | Journal of Applied Toxicology. 19:193-198 |
| ISSN: | 1099-1263 0260-437X |
| DOI: | 10.1002/(sici)1099-1263(199905/06)19:3<193::aid-jat553>3.0.co;2-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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