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Studies on isoniazid-induced hepatotoxicity in rabbits

University of British Columbia

Approximately one-third of the world's population harbors the tuberculosis mycobacterium and it is estimated that tuberculosis kills over 2.5 million persons per year worldwide. Isoniazid is widely used in the prophylaxis and treatment of tuberculosis in this population. A major risk of isoniazid-therapy is the onset of an unpredictable and potentially fatal hepatotoxicity in 1-2% of individuals. Although the existence of this toxicity has been widely recognized for over 25 years, its mechanism remains unknown. Thus, the hepatotoxicity remains neither preventable nor treatable. Our laboratory has developed a reliable model of isoniazid-induced hepatotoxicity in rabbits which closely resembles the toxicity in humans. This model consists of repeated injections of isoniazid over a two day period along with examination of isoniazid-induced pathological changes before, during and after exposure to isoniazid. The purpose of this thesis was to characterize the biochemical and pathological changes induced by isoniazid and to identify and attempt to alter toxicologically important enzymatic steps in the metabolism of isoniazid. The main findings were as follows: 1. Isoniazid causes hepatic cell damage, hepatic steatosis and hypertriglyceridemia in rabbits. 2. Plasma levels of the isoniazid-metabolite hydrazine, but not acetylhydrazine, correlated significantly with the severity of isoniazid-induced hepatic cell damage. 3. Pre- and co-treatment of isoniazid-treated rabbits with L-thyroxine increases the activity of NADPH cytochrome P-450 reductase (reductase). 4. An increase in activity of reductase was associated with a decrease, rather than the expected increase, in the severity of isoniazid-induced hepatotoxicity. 5. Isoniazid administration inhibits cytochrome P-450 (CYP) 1A1/2 and CYP2E1 activities in rabbits. 6. Pretreatment of isoniazid-treated rabbits with bis-p-nitrophenyl phosphate (BNPP) (a proposed inhibitor of isoniazid-amidase which hydrolyses isoniazid and its metabolites to hydrazine) effectively decreased plasma levels of isoniazid-derived hydrazine and decreased the severity of isoniazid-induced hepatic cell damage, hepatic steatosis and hypertriglyceridemia. 7. In vitro studies revealed that BNPP acts as an irreversibly acting non-competitive antagonist (IC50 approximately 2 JUM) of isoniazid-amidase. In conclusion, hydrazine is most likely the main causative agent in isoniazidinduced hepatotoxicity in rabbits. The results in this animal model are in accord with recent data on isoniazid-hepatotoxicity in humans.

Thesis/Dissertation

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2009-04-20

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http://hdl.handle.net/2429/7420

Pharmacology and Therapeutics

University of British Columbia

UBCV

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