Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha.
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.
Roberts
R A
RA
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK. ruth.roberts@zeneca.ctl.com
James
N H
NH
Hasmall
S C
SC
Holden
P R
PR
Lambe
K
K
Macdonald
N
N
West
D
D
Woodyatt
N J
NJ
Whitcome
D
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015894:Genome, Human; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D020025:Peroxisome Proliferators / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha