Relative formation of dichloroacetate and trichloroacetate from trichloroethylene in male B6C3F1 mice.
The hepatocarcinogenicity of trichloroethylene (TRI) has been attributed to the metabolite trichloroacetate (TCA). However, mice also form dichloroacetate (DCA) and trichloroethanol (TCE) as metabolites of TRI. TCA and DCA have both been shown to induce hepatic tumors in mice. This study was undertaken to measure the kinetics of TCA and DCA formation in the B6C3F1 mouse using doses of TRI ranging from 0.38 to 15 mmol/kg and TCA at doses of 0.03 to 0.61 mmol/kg. The formation and elimination of TCA and DCA have been found to be nonlinear with the dose of TRI. Quantifiable levels of DCA were found in blood with doses above 0.76 mmol/kg TRI. The peak concentration of DCA did not show an appreciable change with an increased dose; however, the area under the curve (AUC) increased linearly with respect to the dose of TRI. Both peak concentration and AUC of TCA and TCE increased in a linear manner to a dose of 3.8 mmol/kg. The kinetics of TCA elimination following doses of TCA were similar to those found for TCA following doses of TRI. A significant dose-dependent partitioning of TCA into blood over liver was found at the higher doses of TRI and TCA investigated. Binding of TCA to plasma constituents accounted for this distributional pattern. Prior work has documented that DCA can be formed from TCA. However, the AUC for DCA following TRI exceeds that predicted from the formation of TCA from TRI. Additional pathways would, therefore, appear to account for the formation of DCA. Results from this investigation suggest that sufficient concentrations of DCA appear to be formed and may contribute to the hepatocarcinogenicity of TRI.
Templin
M V
MV
Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman 99164-6510.
Parker
J C
JC
Bull
R J
RJ
D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D014238:Trichloroacetic Acid / Q000493:pharmacokinetics* / Q000633:toxicity; D014241:Trichloroethylene / Q000493:pharmacokinetics* / Q000633:toxicity
D001798:Blood Proteins; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid