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[摘要]：Four isatin-isoniazid derivatives with proven efficacy against resistant strains of Mycobacterium tuberculosis, that had greater lipophilicity than isoniazid were evaluated for effects on hepatic drug metabolizing and chemoprotective enzymes and compared to isoniazid. Following intragastric administration to mice (75 or 150 mg/kg x 3 days), none of the four compounds exhibited hepatotoxicity, and only isoniazid was found to elevate CYP2E1 activity. All compounds slightly elevated Cyp1a1/2 mRNA levels, but these did not result in increased methoxyresorufin demethylase activity. With the exception of isoniazid, approximately twofold elevations in Ugt1a mRNAs (seen with isatin-isoniazid [Ugt1a1, Ugt1a6, Ugt1a9], 1-propynylisatin-isoniazid [Ugt1a1, Ugt1a9], and 1-propylisatin-isoniazid [Ugt1a1]) also did not result in changes in 4-nitrophenol glucuronidation activity. 1-Benzylisatin-isoniazid was the only compound that (1) elevated Ugt2b5 mRNA, and (2) like isoniazid, had no effect on glutathione transferase activities and mRNAs. 1-Propynylisatin-isoniazid elevated glutathione transferase activity toward 1-chloro-2,4-dinitrobenzene, 1-propylisatin-isoniazid decreased the 2.4-kb Gstp transcript, and isatin-isoniazid increased Gsta, Gstm, and the 1.2-kb Gstp transcripts. None of the four compounds affected glutathione peroxidase activity, although 1-propynylisatin-isoniazicl and 1-benzylisatin-isoniazid elevated mRNA transcripts. None of the four compounds affected microsomal epoxide hydrolase or thioredoxin reductase activities but, in parallel, isoniazid, 1-propynylisatin-isoniazid, and 1-propylisatin-isoniazid elevated mRNAs of each. 1-Propynylisatin-isoniazid, 1-propylisatin-isoniazid, and 1-benzylisatin-isoniazid, and isoniazid, elevated quinone oxidoreductase (Nqo1) mRNA, but only 1-propylisatin-isoniazid elevated the activity. Altogether, and despite some changes in mRNA expression, the novel isatin-isoniazid derivatives had only minor effects on mouse hepatic enzyme activities and are worthy of further investigation as possible therapeutic agents likely free of major induction-related drug drug interactions. Drug Dev Res 71:313-322, 2010. (C) 2010 Wiley-Liss, Inc. |
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