Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent.
Administration of the bacterial endotoxin lipopolysaccharide (LPS) causes induction of cytochrome P-450 (CYP) 4A mRNAs in rat liver and kidney. Because induction of the CYP4A subfamily by chemicals requires peroxisome proliferator-activated receptor-alpha (PPARalpha), we determined whether CYP4A induction by LPS also requires PPARalpha by comparing the responses of PPARalpha-null (-/-) and wild-type (+/+) mice. Renal expression of CYP4A10, CYP4A14, and acyl-CoA oxidase was induced by LPS treatment in (+/+) mice, and these effects were absent in the (-/-) mice. In contrast, hepatic expression of CYP4A10 was down-regulated in the (+/+) animals, and no significant induction of acyl-CoA oxidase or CYP4A14 was detected in liver. Expression of the peroxisomal bifunctional enzyme was not significantly affected by LPS treatment. These results indicate that PPARalpha is activated in mouse kidney after LPS treatment and that this leads to modulation of some PPARalpha-regulated genes. However, the species and tissue specificity of these effects suggest that inflammatory pathways may modulate the induction via PPARalpha. Mice pair fed with LPS-treated mice showed no induction of renal CYP4A10 or CYP4A14, indicating that renal CYP4A induction during endotoxemia is not due to hypophagia. Down-regulation of CYP2A5, CYP2C29, and CYP3A11 by LPS was attenuated or blocked in the (-/-) mice, suggesting a role for PPARalpha in CYP down-regulation as well. Finally, we found that clofibrate caused an acute induction of two hepatic acute-phase mRNAs that was only partially dependent on PPARalpha.
Barclay
T B
TB
Department of Pharmacology, Emory University, Atlanta, Georgia, USA.
Peters
J M
JM
Sewer
M B
MB
Ferrari
L
L
Gonzalez
F J
FJ
Morgan
E T
ET
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D015536:Down-Regulation; D019446:Endotoxemia / Q000201:enzymology* / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System