Species differences in carcinogenicity and peroxisome proliferation due to trichloroethylene: a biochemical human hazard assessment.
Trichloroethylene (TRI) administered to mice by gavage for 10 consecutive days at doses of 50-2000 mg/kg body weight elicited dose-dependent increases (up to 700% of control values) of hepatic cyanide insensitive palmitoyl CoA oxidation (a marker of peroxisomal beta-oxidation). No effect was seen on catalase; the other peroxisomal marker examined. Similar experiments with rats demonstrated no effect of TRI on either cyanide insensitive palmitoyl CoA oxidation or catalase. A major metabolite of TRI, trichloroacetic acid (TCA) when administered by gavage for 10 consecutive days at doses of 10-200 mg/kg body weight, stimulated hepatic cyanide insensitive palmitoyl CoA oxidation in both mice (up to 500% of control) and rats (up to 650% of control). Again, no effect upon catalase activity was apparent. The kinetics of biotransformation of TRI to TCA in isolated hepatocytes was markedly species dependent. The 'intrinsic clearance' values (Vmax/Km) for TRI in mouse, rat and human hepatocytes were 3.8 X 10(-6), 1.2 X 10(-7) and 3.25 X 10(-8) L/min/10(6) cells respectively. TCA induced peroxisomal beta-oxidation in mouse and rat hepatocytes, but had no effect upon this enzyme activity in cultured human hepatocytes. It is postulated that the species difference in hepatocarcinogenicity of TRI (mouse positive; rat negative) is due to species differences in peroxisome proliferation which in turn is a result of differences in the rate of formation of TCA from TRI. On this basis it is proposed that TRI presents no significant human hepatocarcinogenic hazard since, human hepatocytes produced TCA at a rate even lower than that of the rat, and TCA was not a peroxisome proliferator in human hepatocytes.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D002374:Catalase / Q000032:analysis; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D014238:Trichloroacetic Acid / Q000096:biosynthesis / Q000494:pharmacology; D014241:Trichloroethylene / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*
D002273:Carcinogens; D010171:Palmitoyl Coenzyme A; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D006899:Mixed Function Oxygenases; D002374:Catalase