Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPAR alpha

Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens th at cause liver enlargement and hepatocarcinogenesis associated with peroxis ome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis. Acyl CoA oxidase (ACO) is a key enzyme of peroxisomal beta-oxid ation and its transcriptional activation by PPs is often used as marker for the rodent response. PPs activate the peroxisome proliferator activated re ceptor-alpha, PPAR alpha. Recent data suggest a role for tumour necrosis fa ctor alpha (TNF alpha). This cytokine appears to be permissive for a PPAR a lpha-dependent growth response to PPs. Humans and guinea pigs appear to be nonresponsive to the adverse effects of PPs noted in rodents. These species differences can be attributed to reduced quantity of full length functiona l PPAR alpha. in human liver and evidence supports the presence of a trunca ted form of PPAR alpha, hPPAR alpha 8/14 in human liver. In addition, speci es differences could be attributed to qualitative differences in the PPAR a lpha-mediated response because the promoter for human ACO differs in sequen ce and activity from the rat equivalent. These data contribute to our under standing of how chemicals may cause tumours in rodents and how this respons e may differ in humans. (C) 2000 published by Elsevier Science Ireland Ltd. All rights reserved.