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Vol. 296, Issue 2, 542-550, February 2001
-Deficient Mice upon Lipopolysaccharide and Clofibrate
Challenges
Department of Biochemistry and Molecular Biology, University of
Texas Medical School at Houston, Houston, Texas (X.M.C., H.W.S.);
Department of Urology, Osaka City University Medical School, Osaka,
Japan (H.K.); Department of Pharmacology, Emory University School of
Medicine, Atlanta, Georgia (T.B.B., E.T.M); and Laboratory of
Metabolism, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland (J.M.P., F.J.G.)
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) 
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
PPAR is partially responsible for this down-regulation. Clofibrate
treatment caused the reduction of hepatic CYP4F16 expression and this
effect was not dependent on PPAR. 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.
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