Inhibitors of cytochrome P-450 augment fever induced by interleukin-1 beta

The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. The cytochrome P450 isoform CYP2J2 was cloned and identified as a potential source of EETs in human endothelial cells. Physiological concentrations of EETs or overexpression of CYP2J2 decreased cytokine-induced endothelial cell adhesion molecule expression, and EETs prevented leukocyte adhesion to the vascular wall by a mechanism involving inhibition of transcription factor NF-κB and IκB kinase. The inhibitory effects of EETs were independent of their membrane-hyperpolarizing effects, suggesting that these molecules play an important nonvasodilatory role in vascular inflammation.

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“…4C). Our findings are also consistent with studies in mice showing augmentation of fever by inhibitors of cytochrome P450 epoxygenases (22,23).…”

supporting

confidence: 92%

Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids

Node

Huo

Ruan

et al. 1999

Science

1,089

1,101

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“…Studies originally conducted by Nakashima et al in the mid 1990’s suggested a role for EFAs in pyresis and the regulation of body temperature [52]. This led to further work supporting the anti-inflammatory effect of the 11,12-EET regioisomer and demonstration of its ability to inhibit the activation of the NFκB pathway [53].…”

Section: Efas Modulate Pain Signalingmentioning

confidence: 99%

Soluble epoxide hydrolase inhibition, epoxygenated fatty acids and nociception

Wagner

Inceoglu

Hammock

2011

Prostaglandins & Other Lipid Mediators

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The soluble epoxide hydrolase (sEH) enzyme regulates the levels of endogenous epoxygenated fatty acid (EFA) lipid metabolites by rapidly degrading these molecules. The EFAs have pleiotropic biological activities including the modulation of nociceptive signaling. Recent findings indicate that the EFAs, in particular the arachidonic acid (AA) derived epoxyeicosatrienoic acids (EETs), the docosahexaenoic acid (DHA) derived epoxydocosapentaenoic acids (EpDPEs) and eicosapentaenoic acid (EPA) derived epoxyeicosatetraenoic acids (EpETEs) are natural signaling molecules. The tight regulation of these metabolites speaks to their importance in regulating biological functions. In the past several years work on EFAs in regard to their activities in the nervous system evolved to demonstrate that these molecules are anti-inflammatory and anti-nociceptive. Here we focus on the recent advances in understanding the effects of sEH inhibition and increased EFAs on the nociceptive system and their ability to reduce pain. Evidence of their role in modulating pain signaling is given by their direct application and by inhibiting their degradation in various models of pain. Moreover, there is mounting evidence of EFAs role in the crosstalk between major nociceptive and anti-nociceptive systems which is reviewed herein. Overall the fundamental knowledge generated within the past decade indicates that orally bioavailable small molecule inhibitors of sEH may find a place in the treatment of a number of diverse painful conditions including inflammatory and neuropathic pain.

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“…Throughout the past few decades the neurobiological effects of EETs have been described albeit sporadically (33, 48–49). Here we expand on the novel hypothesis that a major role of EETs and other EFAs is the attenuation of pain.…”

Section: Efas and Seh Inhibitors Block Inflammatory And Neuropathic Painmentioning

confidence: 99%

“…Since PGE 2 causes both pain and inflammation it was logical to try sEH inhibitors as therapeutics for inflammatory pain (28–29). The initial indication that EETs and possibly other EFAs are powerful anti-inflammatory molecules came from observations made by Nakashima et al, who described the anti-pyretic properties of endogenous epoxygenase metabolites in the brain (48). This was further supported by Node et al who demonstrated a mechanism of action for EETs in vitro involving the NFkB pathway (50).…”

Section: Efas and Seh Inhibitors Block Inflammatory And Neuropathic Painmentioning

confidence: 99%

Epoxygenated Fatty Acids and Soluble Epoxide Hydrolase Inhibition: Novel Mediators of Pain Reduction

Wagner

Inceoglu

Gill

et al. 2010

J. Agric. Food Chem.

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The soluble epoxide hydrolase (sEH) enzyme was discovered while investigating the metabolism of xenobiotic compounds in the Casida laboratory. However an endogenous role of sEH is to regulate the levels of a group of potent bioactive lipids, epoxygenated fatty acids (EFAs) that have pleiotropic biological activities. The EFAs, in particular the arachidonic acid derived EETs, are established autocrine and paracrine messengers. The most recently discovered outcome of inhibition of sEH and increased EFAs are their effects on the sensory system and in particular their ability to reduce pain. The inhibitors of sEH block both inflammatory and neuropathic pain. Elevation of EFAs, both in the central and peripheral nervous systems, blocks pain. Several laboratories have now published a number of potential mechanisms of action for the pain reducing effects of EFAs. Here we provide a brief history of the discovery of the sEH enzyme and argue that inhibitors of sEH through several independent mechanisms display pain reducing effects.

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Inhibitors of cytochrome P-450 augment fever induced by interleukin-1 beta

Cited by 16 publications

References 0 publications

Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids

Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids

Soluble epoxide hydrolase inhibition, epoxygenated fatty acids and nociception

Epoxygenated Fatty Acids and Soluble Epoxide Hydrolase Inhibition: Novel Mediators of Pain Reduction

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