title: A model of isoniazid-induced hepatotoxicity in rabbits.
abstract: Isoniazid (INH) continues to be an effective drug used for chemoprophylaxis and treatment of tuberculosis. Unfortunately, INH is associated with significant hepatotoxicity in up to 2% of individuals exposed, and if this adverse event is not recognized early it can be fatal. Research on INH-induced hepatotoxicity has been hampered by the lack of a suitable animal model that closely resembles the toxicity in humans. The mechanism of INH-induced hepatotoxicity is still unknown. The present study describes the development of a reliable model of INH-induced hepatotoxicity in rabbits. The protocol involves repeated injections of INH over a 2-day period, resulting in significant hepatic necrosis as indicated by elevations of plasma argininosuccinic acid lyase activity. Pretreatment with phenobarbital increased the occurrence of INH-induced hepatic necrosis from approximately 60% (9 out of 15 rabbits) with INH alone to more than 90% (13 out of 14 rabbits). Morphological indices were used to demonstrate the presence of INH-induced hepatotoxicity, and biochemical indices were used to demonstrate both the presence and severity of INH-induced hepatotoxicity in this model. This model may prove useful for further investigations into the mechanism of INH-induced hepatotoxicity.
authors.affiliation: Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: T C
authors.initials: TC
authors.lastname: Sarich
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.forename: S P
authors.initials: SP
authors.lastname: Adams
authors.forename: A I
authors.initials: AI
authors.lastname: Bain
authors.forename: R A
authors.initials: RA
authors.lastname: Wall
authors.forename: J M
authors.initials: JM
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001123:Argininosuccinate Lyase / Q000097:blood; D004195:Disease Models, Animal; D007279:Injections, Subcutaneous; D007538:Isoniazid / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D011817:Rabbits
chemical_list: D001123:Argininosuccinate Lyase; D007538:Isoniazid