Molecular cloning and regulation of expression of two novel mouse CYP4F genes: expression in peroxisome proliferator-activated receptor alpha-deficient mice upon lipopolysaccharide and clofibrate challenges.
Cytochrome P450 4F isoforms catalyze the hydroxylation of eicosanoids such as leukotriene B(4), prostaglandins, and lipoxins as well as hydroxyeicosatetraenoic acids. In the present study, we report the molecular cloning of two novel mouse CYP4F isoforms, CYP4F15 and CYP4F16. Sequence comparison showed that CYP4F15 has 93.5% homology to CYP4F4 and CYP4F16 has 90.8% homology to CYP4F5, therefore they are the orthologs for rat CYP4F4 and CYP4F5, respectively. Both isoforms are expressed in liver and also in extrahepatic tissues but the patterns of expression are slightly different. To elucidate further the regulation and regulatory mechanism of the two isoforms, renal and hepatic CYP4F15 and CYP4F16 expression were analyzed using wild-type (SV/129) mice and peroxisome proliferator-activated receptor (PPAR) alpha null mice with or without challenge by bacterial endotoxin (LPS) or clofibrate. Renal expression of CYP4F15 was induced by LPS and clofibrate in (+/+) mice, and these effects were absent in the (-/-) mice. Renal expression of CYP4F16 was not affected by LPS or clofibrate in (+/+) or (-/-) mice. In contrast, hepatic expression of CYP4F15 and CYP4F16 was significantly reduced by LPS-treatment in (+/+) mice. A lesser reduction was also seen in the (-/-) mice, suggesting that PPARalpha is partially responsible for this down-regulation. Clofibrate treatment caused the reduction of hepatic CYP4F16 expression and this effect was not dependent on PPARalpha. Clofibrate treatment had no effect on hepatic CYP4F15 expression. Together, our data indicate that CYP4Fs are regulated in an isoform-specific, tissue-specific, and species-specific manner.
Cui
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Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Kawashima
H
H
Barclay
T B
TB
Peters
J M
JM
Gonzalez
F J
FJ
Morgan
E T
ET
Strobel
H W
HW
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002994:Clofibrate / Q000494:pharmacology*; D003001:Cloning, Molecular; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D015342:DNA Probes; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
D015342:DNA Probes; D000960:Hypolipidemic Agents; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate