Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: a dose-effect study.
The relationship among dose, metabolism and hepatotoxicity in mice which resulted from subchronic exposure to the chlorinated solvents trichloroethylene (TRI) and perchloroethylene (PER) were examined. Male Swiss-Cox mice received either TRI (0 to 3200 mg/kg/day) of PER (0 to 2000 mg/kg/day) in corn oil by gavage for 6 weeks. Urinary metabolites from individual mice were quantified to estimate the extent to which each compound was metabolized. Four parameters of hepatotoxicity were assessed: liver weight, triglycerides, glucose-6-phosphatase (G6P) activity, and SGPT activity. TRI significantly affected liver weight and G6P activity; PER affected all four parameters. The metabolism of TRI was linearly related to dose through 1600 mg/kg, but then became saturated. The metabolism of PER was saturable. The dose-effect curves of the affected hepatotoxicity parameters of both compounds were nonlinear and resembled the dose-metabolism graph of the corresponding solvent. Plots of the hepatotoxicity data of each compound against total urinary metabolites were linear in all cases, suggesting that the hepatotoxicity of both PER and TRI in mice is directly related to the extent of their metabolism. This pattern is consistent with formation of the toxic intermediate in the primary metabolic pathway of each compound.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000652:urine; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D013750:Tetrachloroethylene / Q000378:metabolism / Q000633:toxicity*; D014238:Trichloroacetic Acid / Q000652:urine; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*; D014280:Triglycerides / Q000378:metabolism
D014280:Triglycerides; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D000410:Alanine Transaminase; D005952:Glucose-6-Phosphatase; D013750:Tetrachloroethylene