Dose-dependent metabolism of trichloroethylene and its relevance to hepatotoxicity in rats.
Fasted male Sprague-Dawley rats pretreated with phenobarbital received an intraperitoneal injection of 0.00, 0.25, 0.50, 0.75, 1.00, 1.50, or 2.00 ml/kg of trichloroethylene (TRI) in corn oil. The metabolic fate of TRI was monitored by measuring its major urinary metabolites 24 hr following the dosing. The hepatotoxic response of TRI was evaluated by determination of the serum transaminase activities (SGOT and SGPT) 24 hr after dosing. Treatment of rats with TRI up to 0.5 ml/kg did not affect the transaminase responses, but significant response was manifested at 0.75 ml/kg dose. Further continuous increases in such responses were induced on exposure to higher doses. Dose-dependent urinary excretions of trichloroethanol and trichloroacetic acid were observed and reached an apparent saturation at 1-1.5 ml/kg dose of TRI. The percentage of dose excreted as trichloroethanol was decreased from 16% at 0.25 ml or 2.8 mmole/kg to 8% at 2 ml or 22.3 mmole/kg dose. The percentage of trichloroacetic acid was decreased from 5 to 2% for the same dose interval. A maximum of only 29% depletion of hepatic glutathione was observed at 2 hr following 1 ml/kg dose of TRI. Similarly, the excretion of urinary mercapturic acid of TRI or thioether was insignificant at any dose level. These results suggest that the conjugation of hepatic glutathione with the electrophilic intermediate of TRI does not seem to be an important determinant for TRI hepatotoxicity nor the major detoxification pathway of its reactive intermediate. TRI produced also a dose-dependent decrease in hepatic microsomal monooxygenase activities as well as cytochrome P-450 content. All these results, when combined, show that there exists an apparent saturable metabolism of TRI involving its activation/deactivation pathways which correspond to an apparent threshold or minimal toxic dose, about 1 ml/kg or 11.15 mmole/kg of TRI for its hepatotoxicity.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D000637:Transaminases / Q000097:blood; D014241:Trichloroethylene / Q000378:metabolism* / Q000633:toxicity
D014241:Trichloroethylene; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D000637:Transaminases; D005978:Glutathione