Species differences in peroxisome proliferation; mechanisms and relevance

Peroxisome proliferators are a class of structurally diverse chemicals, whi ch induce liver carcinogenesis in rodents through interaction and activatio n of the Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha). PPA R alpha agonists elicit a powerful pleiotropic response, which include hypo lipidaemia. We have examined the response of species that are classically u nresponsive to peroxisome proliferators. Whereas hamster responds to PPAR a lpha agonists by hepatomegaly and induction of marker genes, the guinea pig does not undergo hepatomegaly or induction of marker genes, such as CYP4A1 3. Both the hamster and the guinea pig have PPAR alpha, and the guinea pig receptor has been characterised to be fully functional. as demonstrated in reporter gene expression assays. However, the guinea pig PPAR alpha is expr essed at low levels in liver, and the currently favoured hypothesis to expl ain species differences in hepatic peroxisome proliferation invokes the low level of PPAR alpha as the principal determinant of species responsiveness . However, the demonstration that guinea pigs and humans undergo hypolipida emia induced by PPAR alpha-agonists calls into question the mode of action of PPAR alpha agonists in "non-responsive" species. (C) 2000 Elsevier Scien ce B.V. All rights reserved.