HYPERTHYROIDISM INCREASES COVALENT BINDING AND BILIARY-EXCRETION OF 1,1-DICHLOROETHYLENE IN RATS

Distribution, covalent binding, and biliary excretion of 1,1-dichloroe thylene (DCE) were examined in euthyroid (EuT) and hyperthyroid (Hyper T) rats, which are more vulnerable to DCE hepatotoxicity. Male Sprague -Dawley rats were made hyperthyroid by 3 sc injections of thyroxine at 48-h intervals prior to experiments; euthyroid controls received vehi cle injections. A time course study monitored the circulation and excr etion of C-14-DCE label for 24 h after administration of C-14-labeled DCE (50 mg/kg in mineral oil) in serial blood and urine samples. At 24 h, total and covalently bound C-14-label were measured in liver, kidn ey, and lung. Hepatotoxicity of DCE was enhanced in the HyperT rats, a s evidenced by elevated serum activities of aminotransferase and histo pathology, and was associated with increases in circulating metabolite , and in metabolite bound to red blood cells and liver bur not to kidn ey or lung. Hyperthyroidism had little effect on in vitro capacity of hepatic microsomes to convert DCE to reactive intermediates as reflect ed by covalent binding. A biliary excretion study in pentobartibal-ane sthetized rats showed a striking, but transient, increase in toxicant metabolite excretion in bile of HyperT rats during the first 2 h after toxicant administration (C-14-DCE, 100 mg/kg). During the next 2 h, b iliary metabolite excretion by HyperT rats decreased while there was a rise in circulating amounts of total and bound C-14-label. Thus, alth ough hyperthyroidism had little effect on the total extent of DCE meta bolized, this hormonal disturbance may have transiently enhanced metab olite formation and definitely was associated with a lesser ability to detoxify reactive DCE metabolites capable of injuring hepatic cell co nstituents by covalent binding reactions.