title: Trichloroethylene. II. Mechanism of carcinogenicity of trichloroethylene.
abstract: The cancer inducing effect of trichloroethylene (TCE) was studied by various methods. DNA complexing activity and apoptosis inhibition were found to be the key elements of the carcinogenicity of TCE and its metabolites. The ability of TCE to interact with DNA was low, but its incorporation into the RNA and DNA of the brain, testis, pancreas, kidney, liver, lung and spleen, cannot be excluded. Exposure to TCE and its metabolites provides a selective growth advantage to spontaneously occurring mutations in some K- and H-ras oncogenes (as non specific results of secondary DNA or RNA damage). The amount of DNA-TCE adducts was higher in mouse hepatocytes than in rat hepatocytes. These differences may explain the species difference in carcinogenicity of TCE, which was dose dependent (due to metabolism) in mice but independent in rats. The blood level kinetics of TCE confirmed the faster metabolic rate in mice, including peroxisome proliferation and induction in hepatocytes. Dichloroacetic- and trichloroacetic acid were found to be hepatic carcinogens in mice, and the specificity depends on peroxisome proliferation induction. Possibly, TCE and related compounds down regulated apoptosis in mouse liver, and the reduced ability to remove initiated cells by apoptosis could be responsible for liver cancer induction by TCE.
authors.affiliation: Department of Medicinal Chemistry, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Motohashi
authors.forename: H
authors.initials: H
authors.lastname: Nagashima
authors.forename: J
authors.initials: J
authors.lastname: Molnár
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D013329:Structure-Activity Relationship; D014241:Trichloroethylene / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
chemical_list: D002274:Carcinogens, Environmental; D014241:Trichloroethylene; D012313:RNA; D004247:DNA