Mediation of Arachidonic Acid Metabolite(s) Produced by Endothelial Cytochrome P-450 3A4 in Monkey Arterial Relaxation.

Ayajiki, Kazuhide; Fujioka, Hideyuki; Toda, Noboru; Okada, Shigeru; Minamiyama, Yukiko; Imaoka, Shingi; Funae, Yoshihiko; Watanabe, Shuji; Okamura, Tomio

doi:10.1291/hypres.26.237

Cited by 24 publications

(24 citation statements)

References 28 publications

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“…Since the specificity of ketoconazole as a CYP inhibitor may be questionable, we examined the effect of 14,15-EEZE, an EETs antagonist on the response, and observed that 14,15-EEZE markedly inhibited the 'EDHF-type' relaxation induced by 2MeSADP. The present study together with our previous investigations suggests the involvement of endothelium-derived CYP products, probably EETs in the 'EDHF-type' relaxation in monkey arteries (15,17,30). Since EETs antagonist did not abolish the 2MeSADP-induced relaxation, possible involvement of endothelial mediators other than EETs is not excluded.…”

Section: Discussionsupporting

confidence: 60%

Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

et al. 2010

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Abstract.We recently reported endothelium-dependent relaxation caused by nucleotides in the non-human primate cerebral artery. Here, we investigated the endothelium-dependent, nitric oxide-and prostanoid-independent relaxation induced by 2-methylthio-ADP (2MeSADP) in monkey cerebral artery. Mechanical responses of isolated monkey cerebral arteries to the agents were isometrically recorded. In endothelium-intact arterial strips treated with indomethacin plus N G -nitro-L-arginine and partially contracted with prostaglandin F 2α , 2MeSADP (1 nM -10 μM) induced concentration-dependent relaxation that was abolished by removal of endothelium but was not influenced by either carboxy PTIO or 18α-glycyrrhetinic acid. The 2MeSADP-induced relaxation was inhibited by MRS2179 and U73122. The relaxation was markedly suppressed by exposure of the strips to high K + media, but was not affected by glibenclamide. Combination of charybdotoxin plus apamin markedly suppressed the relaxation, whereas iberiotoxin partially attenuated it. Relaxation induced by 2MeSADP was inhibited by arachidonyl trifluoromethyl ketone, ketoconazole, and 14,15-epoxyeicosa-5(Z)-enoic acid. The inhibitors that affected the 2MeSADP-induced relaxation did not influence relaxation caused by sodium nitroprusside or forskolin. These findings indicate that 2MeSADP elicits 'endothelium-derived hyperpolarizing factor (EDHF)-type' relaxation via stimulation of endothelial P2Y 1 receptors in monkey cerebral artery. Furthermore, phospholipase A 2 , cytochrome P450-derived epoxyeicosatrienoic acids and Ca 2+-activated K + channels appear to be involved in the relaxation.

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Section: Discussionsupporting

confidence: 60%

Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

et al. 2010

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“…After transfection of MCF7 cells, 120 clones were isolated by ring cloning under G418 selection and analyzed by quantitative PCR for CYP3A4 expression levels. Two clones, one expressing sequence III (supplemental Table S1) (clone [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and the other sequence IV (supplemental Table S1) (clone [4][5][6][7][8][9][10][11][12][13][14] showing greater than 70% reductions in CYP3A4 mRNA expression by real time PCR and Western analysis, were selected for our studies. Six nontarget clones, NT-1 to NT-6 were isolated using the manufacturer's recommended nontarget sequence (SABiosciences, Frederick, MD).…”

Section: -(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium Bromidementioning

confidence: 99%

“…Of these enzymes, CYP2S1 and 26A1 are linked to retinoid metabolism (7,8), and 4V2 has been linked to myristic acid -hydroxylase activity (9). CYP3A4 is the only enzyme of this group potentially linked to the metabolism of AA to (Ϯ)-5,6-, (Ϯ)-8,9-, (Ϯ)-11,12-, and (Ϯ)-14,15-EET regioisomers, based on a preliminary report (10). Nonetheless, there has been no demonstration in the literature to date that CYP3A4 synthesizes EETs with enantiomeric bias necessary to confirm enzymatic synthesis, in contrast to chemical oxidation.…”

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confidence: 99%

CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

Mitra

Guo

Milani

et al. 2011

Journal of Biological Chemistry

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“…Moreover, CYP-13A12 showed (ω-1)-hydroxylase activity with AA, and also catalysed mid-chain oxidations resulting in a series of regioisomeric hydroxy metabolites as minor products. The metabolite patterns of CYP-13A12 resemble those produced by CYP-33E2 from C. elegans [18], CYP2J2, an epoxygenase highly expressed in the human heart [31,32], and also human CYP3A4 [14]. CYP-13A12, CYP-33E2 and CYP2J2 have in common that they prefer EPA over AA as substrate and show a regioselectivity in favour of 17,18-EEQ as the main EPA-derived metabolite.…”

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confidence: 90%

“…CYP3A4, a CYP enzyme predominantly expressed in the liver, but also in the brain and other extrahepatic tissues [12,13], is the most closely related human homolog of CYP-13A12 (32 % amino acid identity). Human CYP3A4 has been primarily known for its important role in liver microsomal drug metabolism but also contributes to the metabolism of a wide variety of endogenous substrates including the epoxidation of AA (arachidonic acid; C 20:4, n−6 ) and anandamide [14,15]. Further work revealed also the emb-8 gene, encoding the worm's homolog of mammalian CPRs (NADPH-CYP reductase) [16], as essential for the O2-ON response [5].…”

Section: Introductionmentioning

confidence: 99%

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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Mediation of Arachidonic Acid Metabolite(s) Produced by Endothelial Cytochrome P-450 3A4 in Monkey Arterial Relaxation.

Cited by 24 publications

References 28 publications

Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

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

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