Abstract
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.
Footnotes
- Received June 29, 2000.
- Accepted August 28, 2000.
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Send reprint requests to: Dr. Henry W. Strobel, Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, P.O. Box 20708, Houston, TX 77030. E-mail:henry.w.strobel{at}uth.tmc.edu
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This work is supported by Grants MH58297 and GM46897 (to E.T.M.) from the National Institute of Mental Health, Department of Health and Human Services, and U.S. Army Grant DAMD-17-98-1-8002 “Disaster Relief and Emergency Medical Service” project. The data presented here form part of the dissertation of Xiaoming Cui submitted to the faculty of The University of Texas Health Science Center at Houston, Graduate School of Biomedical Sciences in partial fulfillment of the requirements for the Doctor of Philosophy degree.
- U.S. Government
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