Young Scientists Award Lecture 1983: Investigations into the Mechanism of Coumarin-Induced Hepatotoxicity in the Rat

Publisher Website
Google Scholar
Abstract
The administration of single doses of coumarin to the rat was found to produce hepatic centrilobular necrosis and also to depress a number of hepatic enzyme activities within 24 h. Coumarin-induced liver damage was diminished by pretreatment with cobaltous chloride but potentiated by the administration of diethyl maleate. Hepatic reduced non-protein sulphydryl levels were rapidly depleted following coumarin treatment whereas urinary mercapturic acid excretion was enhanced suggesting the formation of a coumarin metabolite or metabolites hitherto undetected in this species. In in vitro studies [3–14C]coumarin was converted by rat hepatic microsomes to reactive intermediates which became bound covalently to microsomal proteins. Additional studies established that the formation of reactive metabolites was a cytochrome P-450 dependent process and that macro-molecular binding could be inhibited by sulphydryl compounds (including reduced glutathione) and hepatic cytosol fractions. These results demonstrate that coumarin-induced hepatotoxicity in the rat is likely to be mediated via one or more reactive metabolites generated by cytochrome P-450 dependent enzymes and that reduced glutathione and other thiol agents constitute a detoxification pathway.