RT Journal Article
SR Electronic
T1 Molecular Cloning and Regulation of Expression of Two Novel Mouse CYP4F Genes: Expression in Peroxisome Proliferator-Activated Receptor α-Deficient Mice upon Lipopolysaccharide and Clofibrate Challenges
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 542
OP 550
VO 296
IS 2
A1 Xiaoming Cui
A1 Hidenori Kawashima
A1 Thomas B. Barclay
A1 Jeffrey M. Peters
A1 Frank J. Gonzalez
A1 Edward T. Morgan
A1 Henry W. Strobel
YR 2001
UL http://jpet.aspetjournals.org/content/296/2/542.abstract
AB Cytochrome P450 4F isoforms catalyze the hydroxylation of eicosanoids such as leukotriene B4, 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) α 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 PPARα is partially responsible for this down-regulation. Clofibrate treatment caused the reduction of hepatic CYP4F16 expression and this effect was not dependent on PPARα. 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.