Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences

Peroxisome proliferators (PPs), such as diethylhexylphthalate (DEHP), const itute a diverse class of chemicals with many therapeutic, industrial and en vironmental applications. In rodents, PPs are nongenotoxic hepatocarcinogen s, raising concerns regarding the potential of PPs to harm human health. Ho wever, humans differ from rodents in their response to PPs and the weight o f evidence supports the supposition that PPs do not pose a carcinogenic ris k to humans. The effects of PPs in the rodent are mediated by peroxisome pr oliferator activated receptor alpha (PPAR alpha). PPAR alpha predominates i n the liver whereas another isoform PPAR gamma predominates in adipose tiss ue and in the immune system. This tissue-specific pattern of PPAR alpha exp ression is consistent with a role for PPAR alpha but not PPAR gamma or PPAR beta in PP-induced rodent hepatocarcinogenesis. Humans, marmosets and guin ea-pigs appear refractory or less responsive to the adverse liver effects o f PPs. However, humans give a therapeutic response to the fibrate PPs via a n alteration in lipid metabolism mediated by PPAR alpha. Such marked specie s differences may be explained by quantity of PPAR alpha and/or the quality of the PPAR alpha-mediated response. The lower expression of full-length f unctional PPAR alpha in humans could be attributed to the presence of a tru ncated, inactive form of PPAR alpha, which appears to be present in most in dividuals examined to date. In addition, there are species differences in s equence and responsiveness of the acyl CoA oxidase (ACO) gene promoter, sug gesting that even in the presence of sufficient PPAR alpha, the human equiv alent of rodent genes associated with peroxisome proliferation may remain i nactive.