Epoxygenases and peroxisome proliferator‐activated receptors in mammalian vascular biology

Wray, Jessica A.; Bishop‐Bailey, David

doi:10.1113/expphysiol.2007.038612

Cited by 49 publications

(30 citation statements)

References 75 publications

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“…EETs have been shown to have potent vasodilatory and anti-inflammatory functions (Wray and Bishop-Bailey, 2008). Because CYP2C8 has also been detected in endothelial cells and arteries, oxidation of arachidonic acid to produce 11,12-and 14,15-EETs may play vasodilatory and anti-inflammatory roles (Delozier et al, 2007;Wray and Bishop-Bailey, 2008). This study also indicates the possibility of a previously underrepresented drug-drug interaction due to upregulation of CYP2C8 by hypolipidemic (fibrates and WY14643) and antidiabetic (rosiglitazone) drugs.…”

Section: Cyp2c8 Is a Novel Target Of Ppara In Human Livermentioning

confidence: 57%

“…Because CYP2C8 is involved in the metabolism of fatty acids, it is reasonable to suggest that, like CYP4A, induction of endogenous CYP2C8 by PPARa may serve a role in the oxidative metabolism of arachidonic acid to EETs. EETs have been shown to have potent vasodilatory and anti-inflammatory functions (Wray and Bishop-Bailey, 2008). Because CYP2C8 has also been detected in endothelial cells and arteries, oxidation of arachidonic acid to produce 11,12-and 14,15-EETs may play vasodilatory and anti-inflammatory roles (Delozier et al, 2007;Wray and Bishop-Bailey, 2008).…”

Section: Cyp2c8 Is a Novel Target Of Ppara In Human Livermentioning

confidence: 99%

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CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

Makia

Goldstein

2016

Molecular Pharmacology

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Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor a (PPARa), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARa in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARa response element located at position 22109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARa to this PPARa response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARa, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators.

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Section: Cyp2c8 Is a Novel Target Of Ppara In Human Livermentioning

confidence: 57%

Section: Cyp2c8 Is a Novel Target Of Ppara In Human Livermentioning

confidence: 99%

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

Makia

Goldstein

2016

Molecular Pharmacology

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“…The mRNA expression of FASN was potently reduced in Indo-and FO + Indo-treated mice. Although the protein Regarding the CYP pathways, AA can be metabolized by the CYP2C family to epoxy eicosatrienoic acid, which is a potent anti-infl ammatory mediator ( 34 ) and a strong PPAR agonist ( 35 ). Moreover, it has been recently shown that such epoxy derivatives can be produced from n-3 fatty acids ( 36,37 ).…”

Section: Discussionmentioning

confidence: 99%

Fish oil and indomethacin in combination potently reduce dyslipidemia and hepatic steatosis in LDLR −/− mice

Ganesan

Milne

Webb

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Dyslipidemia, which is characterized by elevated cholesterol or triglycerides, is a major risk factor for coronary heart disease (as reviewed in Ref. 1 ). One of the most studied forms of dyslipidemia is familial hypercholesterolemia (FH) caused by genetic factors. Although homozygous FH is a rare condition, heterozygous FH occurs in approximately 1 in 500 people and can cause premature atherosclerotic disease (as reviewed in Ref. 2 ). Combination therapy is commonly used in clinical practice to improve hypercholesterolemia. The most commonly used combination therapy consists of statins with fi brates or niacin. However, this combination has limited additive effect on LDL cholesterol levels. Moreover, the poor tolerance of niacin and the statin-induced side effects (e.g., muscle toxicity) limit the use of this combination (as reviewed in Refs. 3 and 4 ). In addition to dyslipidemia, infl ammation by itself can lead to increased risk of coronary heart disease. Therefore, a therapeutic regimen that has the potential to reduce dyslipidemia and infl ammation would be more benefi cial in reducing cardiovascular events than treatments aimed at improving dyslipidemia alone.Fish oil (FO) containing n-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid

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“…There have been numerous reports comparing the effects of PPARa and PPARg activation with the effects of the EETs on vascular cell proliferation, migration, and inflammation (Wray and Bishop-Bailey, 2008). Different regioisomers may even target different PPAR isoforms because v-hydroxylated 14,15-EET and 14,15-DHET (Cowart et al, 2002;Fang et al, 2005) as well as 8,9-EET and 11-12-EET Wray et al, 2009) are reported to bind with a high affinity to PPARa, whereas the EETs generated in endothelial cells in response to fluid shear stress target PPARg .…”

Section: Membrane Epoxyeicosatrienoic Acid Receptorsmentioning

confidence: 99%

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

Fleming

2014

Pharmacological Reviews

128

115

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Epoxygenases and peroxisome proliferator‐activated receptors in mammalian vascular biology

Cited by 49 publications

References 75 publications

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

Fish oil and indomethacin in combination potently reduce dyslipidemia and hepatic steatosis in LDLR −/− mice

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

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