Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis

Michelle L. O'Brien, Brett T. Spear, Howard P. Glauert

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations


In this review, the evidence about the role of oxidative stress in the induction of hepatocellular carcinomas by peroxisome proliferators is examined. The activation of PPAR-α by peroxisome proliferators in rats and mice may produce oxidative stress, due to the induction of enzymes like fatty acyl coenzyme A (CoA) oxidase (AOX) and cytochrome P-450 4A1. The effect of peroxisome proliferators on the antioxidant defense system is reviewed, as is the effect on endpoints resulting from oxidative stress that may be important in carcinogenesis, such as lipid peroxidation, oxidative DNA damage, and transcription factor activation. Peroxisome proliferators clearly inhibit several enzymes in the antioxidant defense system, but studies examining effects on lipid peroxidation and oxidative DNA damage are conflicting. There is a profound species difference in the induction of hepatocellular carcinomas by peroxisome proliferators, with rats and mice being sensitive, whereas species such as nonhuman primates and guinea pigs are not susceptible to the effects of peroxisome proliferators. The possible role of oxidative stress in these species differences is also reviewed. Overall, peroxisome proliferators produce changes in oxidative stress, but whether these changes are important in the carcinogenic process is not clear at this time.

Original languageEnglish
Pages (from-to)61-88
Number of pages28
JournalCritical Reviews in Toxicology
Issue number1
StatePublished - Jan 2005


  • Antioxidants
  • Lipid peroxidation
  • Oxidative DNA damage
  • Transcription factors

ASJC Scopus subject areas

  • Toxicology


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