Investigations into the mechanism of coumarin-induced hepatotoxicity in the rat.

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 macromolecular 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.