Hyperthyroidism increases covalent binding and biliary excretion of 1,1-dichloroethylene in rats.
Distribution, covalent binding, and biliary excretion of 1,1-dichloroethylene (DCE) were examined in euthyroid (EuT) and hyperthyroid (HyperT) 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 vehicle injections. A time course study monitored the circulation and excretion of 14C-DCE label for 24 h after administration of 14C-labeled DCE (50 mg/kg in mineral oil) in serial blood and urine samples. At 24 h, total and covalently bound 14C-label were measured in liver, kidney, and lung. Hepatotoxicity of DCE was enhanced in the HyperT rats, as evidenced by elevated serum activities of aminotransferase and histopathology, and was associated with increases in circulating metabolite, and in metabolite bound to red blood cells and liver but not to kidney or lung. Hyperthyroidism had little effect on in vitro capacity of hepatic microsomes to convert DCE to reactive intermediates as reflected by covalent binding. A biliary excretion study in pentobarbital-anesthetized rats showed a striking, but transient, increase in toxicant metabolite excretion in bile of HyperT rats during the first 2 h after toxicant administration (14C-DCE, 100 mg/kg). During the next 2 h, biliary metabolite excretion by HyperT rats decreased while there was a rise in circulating amounts of total and bound 14C-label. Thus, although hyperthyroidism had little effect on the total extent of DCE metabolized, this hormonal disturbance may have transiently enhanced metabolite formation and definitely was associated with a lesser ability to detoxify reactive DCE metabolites capable of injuring hepatic cell constituents by covalent binding reactions.
Kanz
M F
MF
Department of Pathology, University of Texas Medical Branch, Galveston 77555-0605.
Kaphalia
L
L
Mohsin
S
S
Taj
Z
Z
Moslen
M T
MT
D000818:Animals; D001646:Bile / Q000378:metabolism*; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006980:Hyperthyroidism / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004000:Dichloroethylenes; C029297:vinylidene chloride