Increases in Levels of Epoxyeicosatrienoic and Dihydroxyeicosatrienoic Acids (EETs and DHETs) in Liver and Heart in Vivo by 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-Dioxin (TCDD) and in Hepatic EET:DHET Ratios by Cotreatment with TCDD and the Soluble Epoxide Hydrolase Inhibitor AUDA

Diani-Moore, Silvia; Ma, Yuliang; Gross, Steven S.; Rifkind, Arleen B.

doi:10.1124/dmd.113.055368

Cited by 20 publications

(13 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, their induction should elevate levels of EETs. This observation was supported by Diani-Moore et al, (2014) who demonstrated that the P450 1A inducer TCDD can increase the production of EETs and its metabolite DHETs in livers of chick embryos. Further, they reported that cotreatment with the sEH inhibitor AUDA increases the ratio of EET: DHET suggesting that stabilizing EETs can alter biology influenced by the epoxides.…”

Section: Discussionmentioning

confidence: 72%

“…Furthermore, a number of AhR-activators including TCDD and OME increased levels of various epoxy and dihydroxy metabolites in chick embryos (Diani-Moore et al, 2006). This effect was enhanced by combining TCDD with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a well characterized sEHI (Diani-Moore et al, 2014) suggesting the feasibility of modulating EET levels by augmenting their synthesis through inducing P450s and minimizing their metabolism by sEH inhibition.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Goswami

Inceoglu

Yang

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME + TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Goswami

Inceoglu

Yang

et al. 2015

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…Clearly, there are pools of quantifiable intra- and extra-cellular, free acid EpFAs both of which are stabilized and augmented by sEH inhibitors. Tetrachlorodioxin and other xenobiotics induce cytochrome P450 enzymes usually studied for their role in xenobiotic metabolism, sufficiently that they contribute to titers of EpFAs [18]. Since the 2C and 2J as well as a variety of other cytochrome p450s will oxidize multiple unsaturated fatty acids, it is not surprising that the EpFA produced depends in part on the diet as well as the circulating and stored lipids.…”

Section: Novel Paths To Positively Modulating Epfa Titersmentioning

confidence: 99%

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

Inceoglu

Bettaieb

Haj

et al. 2017

Prostaglandins & Other Lipid Mediators

View full text Add to dashboard Cite

The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial – ROS – ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles.

show abstract

“…Alternatively, this could conceivably be due to transport of these metabolites from other organs in the blood. Transport of such metabolites in the circulation is known to occur (Diani-Moore et al 2014). …”

Section: Enzymes Responsible For the Tcdd-mediated Increases In Oxylimentioning

confidence: 99%

“…Previously, Dalton and coworkers showed that TCDD exposure increased the levels of three cyclooxygenase-derived arachidonic metabolites in the urine of mice (Dalton et al 2001). More recently, Diani-Moore and coworkers have reported that TCDD increased the levels of EETs and DHETs in the heart and liver of chick embryos (Diani-Moore et al 2014). …”

Section: Enzymes Responsible For the Tcdd-mediated Increases In Oxylimentioning

confidence: 99%

The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids

Hankinson

2016

Drug Metabolism Reviews

View full text Add to dashboard Cite

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) is the prototype of a large number of non-genotoxic carcinogens, dietary phytochemicals and endogenous metabolites that act via binding the aryl hydrocarbon receptor (AHR). The TCDD-liganded AHR massively upregulates CYP1A1, CYP1A2 and CYP1B1 in many mammalian organs. We demonstrated that TCDD treatment markedly increases the levels of several epoxides and diol metabolites of the epoxides of both ω-6 and ω-3 polyunsaturated fatty acids (PUFA) in the liver and lungs of mice, in an aryl hydrocarbon receptor-dependent fashion, and most likely via the activities of the CYP1 family members. ω-6 epoxides are known to stimulate tumor growth, angiogenesis, and metastasis in mice. Interestingly, ω-3 epoxides have the opposite effect on these parameters. TCDD and other AHR agonists may, therefore, impact angiogenesis, growth and metastasis of tumors in either a positive or negative way, depending on the relative levels of ω-6 epoxides and ω-3 epoxides generated in the host and/or tumor cells. This is of potential relevance to carcinogenesis by AHR agonists in the human, since the human population is exposed to widely varying ω6:ω3 PUFA ratios in the diet.

show abstract

Increases in Levels of Epoxyeicosatrienoic and Dihydroxyeicosatrienoic Acids (EETs and DHETs) in Liver and Heart in Vivo by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and in Hepatic EET:DHET Ratios by Cotreatment with TCDD and the Soluble Epoxide Hydrolase Inhibitor AUDA

Cited by 20 publications

References 45 publications

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors

The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids

Contact Info

Product

Resources

About