1,1-Dichloroethylene hepatotoxicity: hypothyroidism decreases metabolism and covalent binding but not injury in the rat.
Our objective was to determine if the previously reported protective effect of hypothyroidism against 1,1-dichloroethylene hepatotoxicity was associated with a change in distribution and covalent binding. Sprague-Dawley male rats were made hypothyroid (HypoT) by surgical thyroidectomy 2 weeks prior to studies and compared to euthyroid (EuT) rats. Hypothyroidism decreased body weights and liver to body weight ratios while mitochondrial non-protein sulfhydryl groups and cytosolic alcohol dehydrogenase activities were increased by 50%. Rats received a single oral dose of 100 mg [14C]1,1-dichloroethylene (DCE)/kg in mineral oil and were killed at 2, 4, 12 or 24 h; controls received mineral oil only. More rapid liver injury, as measured by serum alanine aminotransferase activity and histology, was present at 2 and 4 h after DCE in HypoT than EuT rats, but a similar magnitude of injury was evident at 12 and 24 h. DCE decreased liver non-protein sulfhydryl groups to a comparable extent in HypoT and EuT rats. Cytosolic glutathione S-transferase and alcohol dehydrogenase activities were decreased only in HypoT rats after DCE. HypoT rats excreted approximately 30% less total [14C]DCE-derived label in urine and their livers, kidneys and lungs consistently contained slightly less covalently bound [14C]DCE-derived label. In contrast, between 1 and 4 h after DCE, greater amounts of acid-soluble and acid-precipitable [14C]DCE-derived label were recovered in red blood cells of HypoT rats. Our results indicate that hypothyroidism did not protect against oral DCE hepatotoxicity but was associated with a more rapid injury at early times. Concurrently, hypothyroidism was found to change the fate of [14C]DCE with higher amounts of 14C-label recovered at early times in red blood cells while less 14C-label was excreted in urine and bound to liver.
Kanz
M F
MF
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
Taj
Z
Z
Moslen
M T
MT
D000284:Administration, Oral; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004000:Dichloroethylenes / Q000493:pharmacokinetics / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013965:Thyroidectomy; D013974:Thyroxine / Q000097:blood; D014018:Tissue Distribution
D004000:Dichloroethylenes; C029297:vinylidene chloride; D000426:Alcohol Dehydrogenase; D005982:Glutathione Transferase; D013974:Thyroxine