Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha
| Autor: | Douglas A. West, Peter R. Holden, Ruth A. Roberts, N.J Woodyatt, Neil Macdonald, Neil H. James, Susan C. Hasmall, D Whitcome, Kevin G. Lambe |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Programmed cell death
medicine.medical_specialty Guinea Pigs Peroxisome Proliferation Receptors Cytoplasmic and Nuclear Apoptosis Biology Toxicology medicine.disease_cause Polymerase Chain Reaction Species Specificity Internal medicine medicine Acyl-CoA oxidase Animals Humans Carcinogen Base Sequence Genome Human Tumor Necrosis Factor-alpha Liver Neoplasms General Medicine Peroxisome Rats Endocrinology medicine.anatomical_structure Liver Hepatocyte Cancer research Peroxisome Proliferators Carcinogenesis Transcription Factors |
| Zdroj: | Toxicology letters. |
| ISSN: | 0378-4274 |
| Popis: | 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, PPARalpha. Recent data suggest a role for tumour necrosis factor alpha (TNFalpha). This cytokine appears to be permissive for a PPARalpha-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 PPARalpha in human liver and evidence supports the presence of a truncated form of PPARalpha, hPPARalpha8/14 in human liver. In addition, species differences could be attributed to qualitative differences in the PPARalpha-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. |
| Databáze: | OpenAIRE |
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