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Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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Appendix E Peroxisome Proliferators and Liver Cancer
Pages 418-426

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From page 418...
... . Peroxisome proliferators are a diverse group of chemicals that include the fibrate class of hypolipidemic drugs (e.g., clofibrate, ciprofibrate)
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From page 419...
... Cytosol protein induction (acyl-CoA hydrolase, malic enzyme, fatty acid binding protein) Other characteristics Species differences: (rat, mouse > hamster, guinea pig > rabbit, dog, of biochemical changes monkey)
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From page 420...
... Peroxisome proliferator response elements, consisting of imperfect direct repeats of the sequence TGACCT spaced by a single base pair, have been identified in the upstream regulatory sequences of several PPAR target genes. The ligand 9-cis-retinoic acid enhances PPAR action by activating the retinoid X receptor, which forms a heterodimer with PPAR and binds to the peroxisome proliferator response elements to induce gene transcription.
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From page 421...
... . Nonhuman primates and humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by PPAR agonist drugs (fibrates)
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From page 422...
... . The other randomized clinical trial was conducted by the World Health Organization to determine whether clofibrate would lower the incidence of ischemic heart disease in men.
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From page 423...
... Interestingly, large increases in the expression of marker mRNAs and proteins, including peroxisomal acyl-CoA oxidase, are not found in human and nonhuman primate hepatocytes treated with these chemicals in vitro. These observations are consistent with a recent study demonstrating the lack of an increase in acyl-CoA oxidase mRNA in human liver samples from 48 patients treated with one of several fibrates (bezafibrate, fenofibrate, or gemfibrozil)
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From page 424...
... Evidence from an in vivo model suggests that there could be considerably more similarities in PPAR target genes among humans and rodents. The weight of evidence suggests that this mode of action would be plausible in humans because they possess PPAR in sufficient quantities to mediate the human hypolipidemic response to therapeutic fibrate drugs.
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From page 425...
... . Further, a meta-analysis of the results from six clinical trials on clofibrate found no excess cancer mortality.
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  • organization trial

  • species differences
  • hypolipidemic drugs
  • fibrate class
  • hypolipidemic response
  • genes activated

  • strong evidence
  • various hypolipidemic
  • recently developed
  • humanized ppar
  • clofibrate treated

  • available epidemiologic
  • human tumorigenicity
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  • ppar ligands
  • clofibrate comprising

  • human ppar
  • fibrate drugs
  • cancer concluded
  • provide strong
  • tumorigenicity resulting


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