Role of cytochromeP-450 in endogenous antipyresis

Abstract

In previous reports, we (15, 18) and others (29) demonstrated data showing that various inhibitors of cytochrome P-450/epoxygenase augment fever in rats and mice, indicating that the enzyme may be involved in endogenous antipyresis. The aim of this study was to further test the hypothesis that the P-450-dependent epoxygenase pathway of arachidonic acid is part of the homeostatic system to control the height of fever. Sprague-Dawley rats were implanted with biotelemeters to monitor body temperature. Fever was induced by intraperitoneal injection of lipopolysaccharide (LPS; 80 microg/kg). We demonstrate that intraperitoneal administration of P-450 inducers (bezafibrate and dehydroepiandrosterone, 10 and 100 mg/kg) before LPS reduced fever in rats in a dose-dependent manner. In complementary experiments, rats were implanted with brain cannulas in addition to the biotelemeters. Various isomers of epoxyeicosanoids were administered into the lateral ventricle at doses of 0.01 to 10 microg/rat to test their influence on LPS-induced fever in rats. Four of five isomers were antipyretic in a dose-dependent manner. The most potent antipyretic isomers were 11, 12-epoxyeicosatrienoic acid (EET) followed by 14,15-EET, 8,9-EET, and 12(R) hydroxyeicosatetraenoic acid. These data support the hypothesis that the cytochrome P-450/epoxygenase pathway of arachidonate metabolism is part of the endogenous antipyretic system.

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

“…Among these metabolites, EET is the putative endothelium-derived hyperpolarization factor, which exerts anti-inflammatory and antihypertensive effects in the cardiovascular system (Makita et al, 1994;Node et al, 1999;Kozak et al, 2000;Zeldin, 2001;Spector et al, 2004;Spiecker and Liao, 2005;Schmelzer et al, 2005;Fleming and Busse, 2006). EETs and EpOMEs are short-lived AA and LA metabolites that are converted by the enzyme soluble epoxide hydrolase (sEH) to pro-inflammatory dihydroeicosatrienoic acids (DHETs) and dihydroxyoctadecenoic acids (DiHOMEs), respectively (Zeldin et al, 1993;Fang et al, 2004).…”

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

“…EETs are products of cytochrome P450 epoxygenase, mainly CYP2C8 in human liver (20,21); they are endowed with important vasodilatating and antiinflammatory properties and serve as components of cell signaling cascades (22)(23)(24)(25)(26). EETs were shown to accumulate in alcoholic liver disease in rat (27) and increased in the rat kidney during liver cirrhosis (28).…”

Soluble Epoxide Hydrolase: Potential Target for Inflammation and Inflammation-Driven Cancer

“…EETs possess antiinflammatory properties and can attenuate monocyte infiltration. 11, 12-EET can inhibit IKK-mediated phosphorylation of IB, maintaining NF-B in an inactive state [9,10]. The anti-inflammatory effects of EETs were found to be associated with inhibition of leukocyte adhesion to the vascular wall by downregulation of transcription factor NFκB.…”

“…EET is synthesized in the endothelium cells and plays a role as an endothelium-dependent hyperpolarizing factor (EDHF) under certain conditions in circulation [3]. EETs have diverse biological functions and have been found to play an important role in modulating hypertension and following renal damage, acute inflammation and inflammatory pain [4][5][6][7][8][9][10] which are essential for physiologic and pathologic processes in the body. Soluble epoxide hydrolase (sEH) is an enzyme that metabolizes endogenous and/or exogenous epoxide-containing compounds to their corresponding diols and/or glycols by catalyzing the addition of water to the epoxide moiety.…”

“…EETs have several physiologic functions including vasodilation , anti-inflammation effects, angiogenesis, cell proliferation , neuron and somatotrophs hormone release, G protein signaling, ion channel activity, and a variety of effects associated with modulation of NFκB [9,10,21,22]. EETs can produce vasodilation of small vascular beds in many different organs including the heart, intestine, and kidney.…”