Rapid, substrate-specific, and dose-dependent deactivation of liver cytosolic glutathione S-transferases in vivo by 1,1-dichloroethylene.
Administration of 200 mg 1,1-dichloroethylene (1,1-DCE)/kg to fasted male rats rapidly decreased liver cytosolic glutathione (GSH) S-transferase activities by half within 1 hr. This early decrease was not associated with increased serum activities of this soluble enzyme and is considered due to enzyme deactivation. The early decrease in enzyme activities was concomitant with a three-fourths depletion of cytosolic GSH and preceded changes in cytochrome P-450 and the onset of liver cytotoxicity, both of which occurred abruptly between 2 and 3 hr. Substantial changes in GSH S-transferase activities at 4 hr were produced only by severely hepatotoxic doses of 1,1-DCE. The early decrease in hepatic GSH S-transferase activities was selective for substrates dichloronitrobenzene, chlorodinitrobenzene and 1,2-epoxy-3-(p-nitrophenoxy)-propane with apparent sparing of activity towards ethacrynic acid. The rapid, selective and dose-dependent deactivation of the hepatic GSH S-transferases could be relevant to the catastrophic hepatotoxicity of 1,1-DCE.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004000:Dichloroethylenes / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; C029297:vinylidene chloride; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase