Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

Konkel, Anne; Schunck, Wolf‐Hagen

doi:10.1016/j.bbapap.2010.09.009

Cited by 192 publications

(197 citation statements)

References 198 publications

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“…Also, the overexpression of the CYP2C9 epoxygenase in, and/or the application of 11,12-or 14,15-EET to monocultures of endothelial cells was associated with angiogenesis Michaelis et al, 2003). In vivo data rapidly followed to support these in vitro findings, with corresponding diols by the soluble epoxide hydrolase (sEH; gene = Ephx2; Konkel and Schunck, 2011;Imig, 2012). The latter enzyme is highly conserved between species, and targeting its expression or activity in mice is an effective way of manipulating fatty acid epoxide and diol levels in vivo (Sinal et al, 2000).…”

supporting

confidence: 49%

“…Even though many CYP isozymes can oxidize a spectrum of -6 and -3 polyunsaturated fatty acids such as retinoic acid, linoleic acid, eicosapentaenoic acid (EPA), and docosahexenoic acid (DHA), they are often referred to as the third pathway of arachidonic acid metabolism, mainly because the most is known about the biological actions of these products (Konkel and Schunck, 2011).…”

mentioning

confidence: 99%

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Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Hu¹,

Popp²,

Frömel³

et al. 2014

J Cell Biol

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supporting

confidence: 49%

mentioning

confidence: 99%

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Hu¹,

Popp²,

Frömel³

et al. 2014

J Cell Biol

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“…In addition, both EPA and DHA compete with AA for the cytochrome P450 (CYP450) enzymes, leading to the formation of important mediators of vasodilation (15) . These EPA-and DHA-derived eicosanoids are likely to exert varying effects within the cardiovascular system.…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

The differential effects of EPA and DHA on cardiovascular risk factors

2011

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Compelling evidence exists for the cardioprotective benefits resulting from consumption of fatty acids from fish oils, EPA (20 :5n-3) and DHA (22 :6n-3). EPA and DHA alter membrane fluidity, interact with transcription factors such as PPAR and sterol regulatory element binding protein, and are substrates for enzymes including cyclooxygenase, lipoxygenase and cytochrome P450. As a result, fish oils may improve cardiovascular health by altering lipid metabolism, inducing haemodynamic changes, decreasing arrhythmias, modulating platelet function, improving endothelial function and inhibiting inflammatory pathways. The independent effects of EPA and DHA are poorly understood. While both EPA and DHA decrease TAG levels, only DHA appears to increase HDL and LDL particle size. Evidence to date suggests that DHA is more efficient in decreasing blood pressure, heart rate and platelet aggregation compared to EPA. Fish oil consumption appears to improve arterial compliance and endothelial function; it is not yet clear as to whether differences exist between EPA and DHA in their vascular effects. In contrast, the beneficial effect of fish oils on inflammation and insulin sensitivity observed in vitro and in animal studies has not been confirmed in human subjects. Further investigation to clarify the relative effects of consuming EPA and DHA at a range of doses would enable elaboration of current understanding regarding cardioprotective effects of consuming oily fish and algal sources of long chain n-3 PUFA, and provide clearer evidence for the clinical therapeutic potential of consuming either EPA or DHA-rich oils.

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“…6) is in line with the general concept of CYP-eicosanoid formation and action as established in mammalian cells [50][51][52][53]. CYP enzymes require molecular oxygen, NADPH, and free C20-PUFAs to catalyse epoxidation and hydroxylation reactions [54].…”

Section: Discussionmentioning

confidence: 61%

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

Keller

Ellieva

Dengke

et al. 2014

Biochemical Journal

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SHORT TITLE:CYP-13A12 of C. elegans is a PUFA-epoxygenase 4 SYNOPSISA specific behavioural response of Caenorhabditis elegans, the rapid increase of locomotion in response to anoxia/reoxygenation called the O2-ON response, has been used to model key aspects of ischemia/reperfusion injury. A genetic suppressor screen demonstrated a direct causal role of CYP-13A12 in this response and suggested that CYP-eicosanoids, which in mammals influence the contractility of cardiomyocytes and vascular smooth muscle cells, might function in C. elegans as specific regulators of the body muscle cell activity. Here we show that co-expression of CYP-13A12 with the NADPH-CYP-reductase EMB-8 in insect cells resulted in the reconstitution of an active microsomal monooxygenase system that metabolised EPA (eicosapentaenoic acid) and also AA (arachidonic acid) to specific sets of regioisomeric epoxy and hydroxy derivatives. Main products included 17,18-EEQ (epoxyeicosatetraenoic acid) from EPA and 14,15-EET (epoxyeicosatrienoic acid) from AA. Locomotion assays showed that the defective O2-ON response of C20-PUFA-deficient, ∆ -12 and ∆ -6 fatty acid desaturase mutants (fat-2 and fat-3, respectively) can be restored by feeding the nematodes AA or EPA, but not ETYA (eicosatetraynoic acid), a non-metabolisable AAanalogue. Already short-term incubation with 17,18-EEQ was sufficient to rescue the impaired locomotion of the fat-3 strain. The endogenous level of free 17,18-EEQ declined during anoxia and was rapidly restored in response to reoxygenation. Based on these results, we suggest that CYP-dependent eicosanoids such as 17,18-EEQ function as signalling molecules in the regulation of the O2-ON response in C. elegans. Remarkably, the exogenously administered 17,18-EEQ increased the locomotion activity already under normoxic conditions and was effective not only with C20-PUFA mutants but to a lesser extent also with wild-type worms. KEYWORDS:Eicosanoids; Polyunsaturated fatty acids; Caenorhabditis elegans; Cytochrome P450; Reoxygenation; 17,18-EEQ ABBREVIATIONS USED: AA, arachidonic acid; CID, collision-induced dissociation; COD, carbon monoxide difference; CPR, NADPH-CYP reductase; CYP, cytochrome P450; DiHETE, dihydroxyeicosatetraenoic acid; DTT, dithiothreitol; EGL, egg laying defect; EGLN, EGL nine; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; EPA, eicosapentaenoic acid; ETYA, eicosatetraynoic acid; GFP, green fluorescent protein; GPCR, G protein-coupled receptor; HEET, hydroxyepoxyeicosatrienoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HIF, hypoxia inducible factor; LC, liquid chromatography; MC, pharyngeal marginal cell; MS, mass spectrometry; NGM, nematode growth medium; PUFA, polyunsaturated fatty acid; RP, reversed-phase 5 INTRODUCTIONOxygen deprivation upon restriction of blood supply followed by reperfusion and concomitant reoxygenation causes tissue injury and is involved in the initiation of various human pathologies including ischemic stroke, myocardial infarction, and ac...

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Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids

Cited by 192 publications

References 198 publications

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

The differential effects of EPA and DHA on cardiovascular risk factors

CYP-13A12 of the nematode Caenorhabditis elegans is a PUFA-epoxygenase involved in behavioural response to reoxygenation

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