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

作者：Roberts RA^*; James NH; Hasmall SC; Holden PR; Lambe K; Macdonald N; West D; Woodyatt NJ; Whitecome D

来源：Toxicology Letters, 2000, 112: 49-57.

DOI：10.1016/S0378-4274(99)00243-X

• peroxisome proliferator
• peroxisome proliferator activated receptor alpha (PPAR alpha)
• tumour necrosis factor alpha (TNF alpha)
• apoptosis
• species differences
• cell proliferation
• nongenotoxic carcinogenesis

Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens that cause liver enlargement and hepatocarcinogenesis associated with peroxisome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis. Acyl CoA oxidase (ACO) is a key enzyme of peroxisomal beta-oxidation and its transcriptional activation by PPs is often used as marker for the rodent response. PPs activate the peroxisome proliferator activated receptor-alpha, PPAR alpha. Recent data suggest a role for tumour necrosis factor alpha (TNF alpha). This cytokine appears to be permissive for a PPAR alpha-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 functional PPAR alpha. in human liver and evidence supports the presence of a truncated form of PPAR alpha, hPPAR alpha 8/14 in human liver. In addition, species differences could be attributed to qualitative differences in the PPAR alpha-mediated response because the promoter for human ACO differs in sequence and activity from the rat equivalent. These data contribute to our understanding of how chemicals may cause tumours in rodents and how this response may differ in humans.

• 出版日期2000-3-15