Expression of PPAR(alpha) in human hepatocytes and activation by trichloroacetate and dichloroacetate.
Dichloroacetate (DCA) and trichloroacetate (TCA) are carcinogenic metabolites of trichloroethylene (TCE), a known hepatocarcinogen in B6C3F1 mice. This hepatocarcinogenesis is believed to result from peroxisome proliferation via PPAR(alpha) and/or stimulation of hepatocyte replication. In this study hPPAR(alpha) levels in six human liver tissues and in a long-term human hepatocyte cell line are compared. PPAR(alpha) levels varied significantly between individual tissues and are generally lower than PPAR(alpha) levels detected in mouse liver. Long-term cultured human hepatocytes display PPAR(alpha) levels only slightly lower than cultured mouse hepatocytes. Transfection studies examining the endogenous hPPAR(alpha) activity revealed little or no receptor activation, even following treatment with high concentrations of peroxisome proliferators. In contrast human hepatocytes transfected with mPPAR(alpha) and mRXR(alpha) display increased expression of PPAR(alpha), and increased PPRE-reporter activity when treated with WY-14,643, TCA, and DCA. This human hepatocyte transfection system is a promising tool for examinin the regulation of genes by PPAR(alpha) from different species.
Walgren
J E
JE
Cell and Molecular Biology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425, USA.
Kurtz
D T
DT
McMillan
J M
JM
D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D010957:Plasmids / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D014238:Trichloroacetic Acid / Q000494:pharmacology*
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid