Molecular analysis of peroxisome proliferation in the hamster.
Three novel P450 members of the cytochrome P450 4A family were cloned as partial cDNAs from hamster liver, characterised as novel members of the CYP4A subfamily, and designated CYP4A17, 18, and 19. Hamsters were treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, methylclofenapate (MCP) or Wy-14,643, and shown to develop hepatomegaly and induction of CYP4A17 RNA, and concomitant induction of lauric acid 12- hydroxylase. This treatment also resulted in hypolipidaemia, which was most pronounced in the VLDL fraction, with up to 50% reduction in VLDL-triglycerides; by contrast, blood cholesterol concentration was unaffected by this treatment. These data show that hamster is highly responsive to induction of CYP4A by peroxisome proliferators. To characterise the molecular basis of peroxisome proliferation, the hamster PPARalpha was cloned and shown to encode a 468-amino-acid protein, which is highly similar to rat and mouse PPARalpha proteins. The level of expression of hamster PPARalpha in liver is intermediate between mouse and guinea pig. These results fail to support the hypothesis that the level of PPARalpha in liver is directly responsible for species differences in peroxisome proliferation.
Choudhury
Agharul I
AI
School of Biology, University of Nottingham, Nottingham NG7 2RD, UK.
Sims
Helen M
HM
Horley
Neill J
NJ
Roberts
Ruth A
RA
Tomlinson
Simon R
SR
Salter
Andrew M
AM
Bruce
Mary
M
Shaw
P Nicholas
PN
Kendall
David
D
Barrett
David A
DA
Bell
David R
DR
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006224:Cricetinae; D042926:Cytochrome P-450 CYP4A / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D006168:Guinea Pigs; D006900:Hydroxylation; D007850:Lauric Acids / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008647:Mesocricetus; D051379:Mice; D008969:Molecular Sequence Data; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D014157:Transcription Factors / Q000819:agonists
D018076:DNA, Complementary; D007850:Lauric Acids; D008055:Lipids; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C030358:lauric acid; D012313:RNA; D042926:Cytochrome P-450 CYP4A