The effect of the trichloroethylene metabolites trichloroacetate and dichloroacetate on peroxisome proliferation and DNA synthesis in cultured human hepatocytes

J. E. Walgren, D. T. Kurtz, J. M. Mcmillan

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Dichloroacetate (DCA) and trichloroacetate (TCA) are metabolites of the environmental contaminant trichloroethylene (TCE) that are thought to be responsible for its hepatocarcino-genicity in B6C3F1 mice. TCA and DCA induce peroxisomal proliferation and are mitogenic in rodent liver. The susceptibility of humans to TCA- and DCA-induced hepatocarcinogenesis is unknown. The current studies were aimed at using both primary and long-term human hepatocyte cultures to study the effects of TCA, DCA, and a potent peroxisome proliferator, WY-14,643, on peroxisomal activity and DNA synthesis in human hepatocytes. Peroxisome proliferation, as assessed by palmitoyl-CoA oxidation activity, was below the limit of detection in all human cell lines tested. However, the human cell lines did display small but significant increases in CYP450 4A11 levels following treatment with WY-14,643 (0.1 mmol/L), indicting that the CYP 4A11 gene may be regulated by peroxisome proliferator-activated receptor α in humans. Similarly to their effect in rodent hepatocyte cultures, TCA and DCA were not complete mitogens in human hepatocyte cultures. In fact, DNA synthesis tended to be significantly decreased following treatment of the cells with WY-14,643, TCA, or DCA. In contrast to rodent hepatocyte responses, TCA and DCA did not increase palmitoyl-CoA oxidation and caused a decrease in DNA synthesis in human hepatocyte cultures, suggesting that humans may not be susceptible to TCA- and DCA-induced hepatocarcinogenesis.

Original languageEnglish (US)
Pages (from-to)257-273
Number of pages17
JournalCell Biology and Toxicology
Volume16
Issue number4
DOIs
StatePublished - Nov 20 2000

Keywords

  • Cell proliferation
  • Dichloroacetate
  • Human hepatocytes
  • Peroxisome proliferation
  • Trichloroacetate
  • Trichloroethylene

ASJC Scopus subject areas

  • Toxicology
  • Cell Biology
  • Health, Toxicology and Mutagenesis

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