Abstract
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 (PPARα) 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 PPARα 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 PPARα transcripts, whereas in human and guinea-pig liver PPARα mRNA was much less abundant. Functional analyses suggested that the guinea-pig PPARα 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 PPARα 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 PPARα ablated the suppression of spontaneous apoptosis by PPs. Taken together, these data show that the `non-responsive' guinea-pig expresses active PPARα in the liver at reduced levels, and may be a useful model for exploring the mechanisms underlying the human response to PPs.
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Received: 31 August 1997 / Accepted: 8 October 1997
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Tugwood, J., Holden, P., James, N. et al. A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: implications for species differences in responses to peroxisome proliferators. Arch Toxicol 72, 169–177 (1998). https://doi.org/10.1007/s002040050483
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DOI: https://doi.org/10.1007/s002040050483