The role of l-thyroxine and hepatic reductase activity in isoniazid-induced hepatotoxicity in rabbits.
There is evidence that hydrazine, a metabolite of isoniazid, plays an important role in the mechanism of isoniazid-induced hepatotoxicity. Hydrazine has been reported to be metabolised by NADPH cytochrome P-450 reductase (reductase) to reactive and potentially toxic intermediates. The present study was designed, using a model of isoniazid-induced hepatotoxicity in rabbits, to determine whether or not reductase plays a role in this toxicity. Although pretreating rabbits with l-thyroxine increased hepatic reductase activity (54% greater than controls), the severity of isoniazid-induced hepatic cell damage (plasma argininosuccinic acid lyase activity) was lower in thyroxine pre-treated animals than in animals treated with isoniazid alone (31.3+/-20 vs 56.0+/-20 Takahara Units, respectively). In addition, pre-treatment with l-thyroxine completely prevented isoniazid-induced hepatic steatosis. In conclusion, contrary to our hypothesis, an increase in reductase activity achieved by pre-treatment with l-thyroxine was associated with a decrease in the severity of isoniazid-induced hepatic cell damage and steatosis in rabbits.
Departments of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
T C
TC
Sarich
S P
SP
Adams
J M
JM
Wright
D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D006834:Hydrazines / Q000633:toxicity; D007538:Isoniazid / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D011817:Rabbits; D013974:Thyroxine / Q000494:pharmacology*
D000995:Antitubercular Agents; D006834:Hydrazines; C029424:hydrazine; D008713:Methimazole; D019392:Cytochrome P-450 CYP2E1; D009251:NADPH-Ferrihemoprotein Reductase; D013974:Thyroxine; D007538:Isoniazid