A peroxisome proliferator-activated receptor-alpha (PPARalpha) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARalpha: implications for species differences in responses to peroxisome proliferators

Arch Toxicol. 1998 Feb;72(3):169-77. doi: 10.1007/s002040050483.


The peroxisome proliferator class of non-genotoxic rodent hepatocarcinogens cause hepatocyte DNA synthesis, peroxisome proliferation and liver tumours when administered to rats and mice, but fail to induce S-phase or peroxisome proliferation in hepatocytes from other species including guinea-pigs, dogs, and primates including humans. There are compelling data that implicate a nuclear receptor, the peroxisome proliferator-activated receptor-alpha (PPARalpha) as an important mediator of the toxic and carcinogenic effects of peroxisome proliferators (PPs). We were interested to consider the guinea-pig as a possible model for human responses to these compounds. This manuscript describes the isolation of a full-length cDNA encoding PPARalpha from guinea-pig liver that is closely related to receptors identified previously in mouse, rat and human. RNA hybridisation experiments suggested that the livers of the PP-responsive rat and mouse contained relatively high levels of PPARalpha transcripts, whereas in human and guinea-pig liver PPARalpha mRNA was much less abundant. Functional analyses suggested that the guinea-pig PPARalpha was able to be activated by PPs. DNA binding studies using in vitro translated proteins showed that the guinea-pig receptor was able to bind specifically to DNA in the presence of the retinoid X receptor (RXR), and transient transfection assays showed that the guinea-pig PPARalpha was capable of being transcriptionally activated in a concentration-dependent fashion by the PPs Wy-14,643 and nafenopin. Also, in guinea-pig primary hepatocyte cultures, a dominant negative repressor of PPARalpha ablated the suppression of spontaneous apoptosis by PPs. Taken together, these data show that the 'non-responsive' guinea-pig expresses active PPARalpha in the liver at reduced levels, and may be a useful model for exploring the mechanisms underlying the human response to PPs.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Guinea Pigs
  • Humans
  • Liver / chemistry*
  • Liver / drug effects
  • Liver / physiology
  • Mice
  • Molecular Sequence Data
  • Rats
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics


  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors