Species differences in peroxisome proliferation; mechanisms and relevance.
Peroxisome proliferators are a class of structurally diverse chemicals, which induce liver carcinogenesis in rodents through interaction and activation of the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha). PPARalpha agonists elicit a powerful pleiotropic response, which include hypolipidaemia. We have examined the response of species that are classically unresponsive to peroxisome proliferators. Whereas hamster responds to PPARalpha agonists by hepatomegaly and induction of marker genes, the guinea pig does not undergo hepatomegaly or induction of marker genes, such as CYP4A13. Both the hamster and the guinea pig have PPARalpha, and the guinea pig receptor has been characterised to be fully functional, as demonstrated in reporter gene expression assays. However, the guinea pig PPARalpha is expressed at low levels in liver, and the currently favoured hypothesis to explain species differences in hepatic peroxisome proliferation invokes the low level of PPARalpha as the principal determinant of species responsiveness. However, the demonstration that guinea pigs and humans undergo hypolipidaemia induced by PPARalpha-agonists calls into question the mode of action of PPARalpha agonists in "non-responsive" species.
Choudhury
A I
AI
School of Biological Sciences, University of Nottingham, University Park, NG7 2RD, Nottingham, UK.
Chahal
S
S
Bell
A R
AR
Tomlinson
S R
SR
Roberts
R A
RA
Salter
A M
AM
Bell
D R
DR
D000818:Animals; D002460:Cell Line; D002992:Clofenapate / Q000633:toxicity*; D006224:Cricetinae; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006529:Hepatomegaly / Q000139:chemically induced; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000235:genetics; D020025:Peroxisome Proliferators / Q000633:toxicity*; D020675:Peroxisomes / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002992:Clofenapate; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A