Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model
- Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2 (Canada)
- Faculty of Dentistry, Centre for the Study of Pain, University of Toronto, Toronto, Ontario, M5G 1G6 (Canada)
Isoniazid is an anti-tuberculosis drug that can cause hepatotoxicity in 20% of patients that is usually associated with an inflammatory response. Hepatocytes when exposed to non-toxic levels of H{sub 2}O{sub 2}, to simulate H{sub 2}O{sub 2} formation by inflammatory cells, became twice as sensitive to isoniazid toxicity. Isoniazid cytotoxicity was prevented by 1-aminobenzotriazole, a non-selective P450 inhibitor or by bis-p-nitrophenyl phosphate (BNPP), an esterase inhibitor. Moreover, the cytotoxicity of hydrazine, the metabolite formed by amidase-catalyzed hydrolysis of isoniazid, was increased 16-fold by a non-toxic H{sub 2}O{sub 2}-generating system. The acetylhydrazine metabolite was found to be much less cytotoxic than hydrazine in this hepatocyte inflammation model. Hydrazine, therefore, seems to be the isoniazid reactive metabolite in this inflammation model. The molecular mechanism of hydrazine-induced cytotoxicity was attributed to oxidative stress as reactive oxygen species (ROS) and protein carbonyl formation occurred before the onset of hepatocyte toxicity. Hydrazine toxicity also involved significant production of endogenous H{sub 2}O{sub 2} which resulted in lysosomal membrane damage and leads to a collapse in mitochondrial membrane potential. These results implicated H{sub 2}O{sub 2}, a cellular mediator of inflammation, as a potential risk factor for the manifestation of adverse drug reactions, particularly those caused by hydrazine containing drugs.
- OSTI ID:
- 21140844
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 229, Issue 1; Other Information: DOI: 10.1016/j.taap.2008.01.002; PII: S0041-008X(08)00008-2; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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