DMD

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on April 12, 2007; DOI: 10.1124/dmd.106.013839

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.106.013839v1
35/7/1126    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ng, V. Y.
Right arrow Articles by Kroetz, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ng, V. Y.
Right arrow Articles by Kroetz, D. L.


Received for publication November 21, 2006.
Revised March 30, 2007.
Accepted for publication April 9, 2007.

Cytochrome P450 Eicosanoids are Activators of Peroxisome Proliferator-Activated Receptor Alpha (PPAR{alpha})

Valerie Y. Ng 1, Yong Huang 1, L. Manmohan Reddy 2, John R. Falck 2, Emil T. Lin 1, Deanna L. Kroetz 3*

1 University of California San Francisco 2 University of Texas Southwestern Medical Center 3 University of California at San Francisco

* Address correspondence to: E-mail: deanna{at}itsa.ucsf.edu

Abstract

Cytochrome P450 (CYP) eicosanoids regulate vascular tone, renal tubular transport, cellular proliferation and inflammation. Both the CYP4A {omega}-hydroxylases, which catalyze 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and soluble epoxide hydrolase (sEH), which catalyzes epoxyeicosatrienoic acid (EET) degradation to the dihydroxyeicosatrienoic acids (DHETs), are induced upon activation of peroxisome proliferator-activated receptor alpha (PPAR{alpha}) by fatty acids and fibrates. In contrast, the CYP2C epoxygenases, which are responsible for EET formation, are repressed after fibrate treatment. We show here that CYP eicosanoids can bind to and activate PPAR{alpha} and result in the modulation of PPAR{alpha} target gene expression. In transactivation assays, 14,15-DHET, 11,2-EET, and 20-HETE were potent activators of PPAR{alpha}. Gel shift assays showed that EETs, DHETs and 20-HETE induced PPAR{alpha}-specific binding to its cognate response element. Expression of apolipoprotein A-I was decreased 70% by 20-HETE whereas apolipoprotein A-II expression was increased up to 3-fold by 11,12-EET, 14,15-DHET, and 20-HETE. In addition, CYP eicosanoids induced CYP4A1, sEH, and CYP2C11 expression, suggesting that they can regulate their own levels. Given that CYP eicosanoids have multiple cardiovascular effects, pharmacological modulation of their formation and/or degradation may yield therapeutic benefits.


Key words: CYP induction, CYP4, eicosanoids, nuclear receptors, peroxisome proliferator-activated receptors


This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
M. Fer, L. Corcos, Y. Dreano, E. Plee-Gautier, J.-P. Salaun, F. Berthou, and Y. Amet
Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism
J. Lipid Res., November 1, 2008; 49(11): 2379 - 2389.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
B. N. M. Zordoky, M. E. Aboutabl, and A. O. S. El-Kadi
Modulation of Cytochrome P450 Gene Expression and Arachidonic Acid Metabolism during Isoproterenol-Induced Cardiac Hypertrophy in Rats
Drug Metab. Dispos., November 1, 2008; 36(11): 2277 - 2286.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. Antoun, S. Goulitquer, Y. Amet, Y. Dreano, J.-P. Salaun, L. Corcos, and E. Plee-Gautier
CYP4F3B is induced by PGA1 in human liver cells: a regulation of the 20-HETE synthesis
J. Lipid Res., October 1, 2008; 49(10): 2135 - 2141.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.