Dose-dependent binding of trichloroethylene to hepatic DNA and protein at low doses in mice.
Trichloroethylene (TCE) is a widely used industrial chemical and a low level contaminant of surface and ground water in industrialized areas. It is weakly mutagenic in several test systems and carcinogenic in rodents. However, the mechanism for its carcinogenicity is not known. We investigated the binding of [1,2-14C]TCE ([14C]TCE) to liver DNA and proteins in male B6C3F1 mice at doses more relevant to humans than used previously. The time course for the binding was studied in animals dosed with 4.1 micrograms [14C]TCE/kg body weight (b.w.) and sacrificed between 0.5 and 120 h after i.p. injection. A dose response study was carried out in mice given [14C]TCE at doses between 2 micrograms/kg and 200 mg/kg b.w. and sacrificed 2 h post-treatment. [14C]TCE associated with the DNA and protein extracts was measured using accelerator mass spectrometry. The highest level of protein binding (2.4 ng/g protein) was observed 1 h after the treatment followed by a rapid decline, indicating pronounced instability of the adducts and/or rapid turnover of liver proteins. DNA binding was biphasic with the first peak (75 pg/g DNA) at 4 h. However, the highest binding (120 pg/g DNA) was found between 24 and 72 h after the treatment. Dose response curves were linear for both protein and DNA binding. The binding of TCE metabolites to DNA was ca. 100-fold lower than to proteins when calculated per unit weight of macromolecules and when measured 2 h post-exposure. This study shows that TCE metabolites bind to DNA and proteins in a dose-dependent manner in liver, one of the target organs for its tumorigenicity. Thus, protein and DNA adduct formation should be considered as a factor in the tumorigenesis of TCE.
Kautiainen
A
A
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
Vogel
J S
JS
Turteltaub
K W
KW
D000818:Animals; D002250:Carbon Radioisotopes / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D013997:Time Factors; D014241:Trichloroethylene / Q000378:metabolism* / Q000633:toxicity
D002250:Carbon Radioisotopes; D002273:Carcinogens; D018736:DNA Adducts; D009711:Nucleotides; D011506:Proteins; D014241:Trichloroethylene; D004247:DNA