title: Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model.
abstract: 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 H2O2, to simulate H2O2 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 H2O2-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 H2O2 which resulted in lysosomal membrane damage and leads to a collapse in mitochondrial membrane potential. These results implicated H2O2, a cellular mediator of inflammation, as a potential risk factor for the manifestation of adverse drug reactions, particularly those caused by hydrazine containing drugs.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Tafazoli
authors.forename: Mariam
authors.initials: M
authors.lastname: Mashregi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006834:Hydrazines / Q000378:metabolism / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced; D007538:Isoniazid / Q000378:metabolism / Q000633:toxicity*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D006834:Hydrazines; D017382:Reactive Oxygen Species; C029424:hydrazine; D006861:Hydrogen Peroxide; C014949:acetylhydrazine; D007538:Isoniazid