Molecular analysis of peroxisome proliferation in the hamster.

Abstract

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.

• Authors: Agharul I Choudhury, Helen M Sims, Neill J Horley, Ruth A Roberts, Simon R Tomlinson, Andrew M Salter, Mary Bruce, P Nicholas Shaw, David Kendall, David A Barrett, David R Bell
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 197 Issue 1 Pg. 9-18 (May 15 2004) ISSN: 0041-008X [Print] United States
• PMID: 15126070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Complementary
• Lauric Acids
• Lipids
• Peroxisome Proliferators
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• lauric acid
• RNA
• Cytochrome P-450 CYP4A

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Cricetinae
• Cytochrome P-450 CYP4A (genetics, metabolism)
• DNA, Complementary (biosynthesis, genetics)
• Enzyme Induction (drug effects)
• Guinea Pigs
• Hydroxylation
• Lauric Acids (metabolism)
• Lipids (blood)
• Liver (drug effects, metabolism)
• Mesocricetus
• Mice
• Molecular Sequence Data
• Peroxisome Proliferators (pharmacology)
• Peroxisomes (drug effects)
• RNA (biosynthesis, genetics)
• Receptors, Cytoplasmic and Nuclear (agonists)
• Transcription Factors (agonists)