PPARα-Mediated Responses in the Rodent Liver: An Holistic Biochemical View

Carcinogenesis through the direct action of genotoxic, DNA damaging chemicals is an established and well-studied paradigm. As yet there are no short term tests available for non-genotoxic rodent carcinogens that do not damage DNA but cause liver tumours in long term rodent bioassays. A key aim is to develop short term in vitro screens for the detection of nongenotoxic carcinogens, and this requires knowledge of the mode or mechanism of action of this class of chemicals. The largest and most chemically diverse family of non-genotoxic hepatocarcinogens is the peroxisome proliferators (PPs) such as hypolipidaemic fibrate drugs, plasticizers used in clingwrap/medical tubing and certain pesticides and solvents. PPs mediate their biological responses via activation of the transcription factor PPAR a (peroxisome proliferator activated receptor a), a member of the nuclear hormone receptor superfamily. PPAR a activation is responsible for the pleiotropic effects of PPs in rodent liver such as the induction of enzymes of the b-oxidation pathway, hepatocyte DNA synthesis, liver enlargement and tumourigenesis. Although much is known, we are far from defining the key cell cycle regulating targets of PPs, due perhaps to past limitations of technology. The technology of proteomics allows quantitative measurement of the expression levels of potentially thousands of individual genes at the protein level on exposure to toxic insult. This is predicted to revolutionise the way many biological systems are investigated. Here we review the current knowledge of proteins involved in the response to peroxisome proliferators and describe the impact of proteomics in this field.