Regiospecific and enantioselective metabolism of 8,9-epoxyeicosatrienoic acid by cyclooxygenase

Zhang, Ji Y.; Prakash, Chandra; Yamashita, Kouwa; Blair, Ian A.

doi:10.1016/0006-291x(92)91619-2

Cited by 40 publications

(24 citation statements)

References 20 publications

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“…For example, overexpression of CYP2J2 in bovine aortic endothelial cells promotes cell proliferation, migration, and tube formation (39). COX-1 is constitutively expressed in most tissues, and therefore we might expect the formation of the 8,9-E-HET metabolites, because their formation by COX-1 was demonstrated in this study and others (17). The combination of COX-1 and COX-2 may lead to the highest levels of E-HETs formed, as we show EETs to be substrates for both enzymes.…”

Section: Resultssupporting

confidence: 56%

“…Compared with 5,6-EET, which is metabolized by COX through the same mechanism as ARA to form an endoperoxide prostaglandin analog, the epoxide position in 8,9-EET blocks endoperoxide formation and instead forms monohydroxyl products on C-11 or C-15. These products are ct-8,9-E-11-HET or ct-8,9-E-15-HET (17). Kinetic plots for 8,9-EET with COX-1 and COX-2 are presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…8,9-EET was metabolized by COX-1 and COX-2 to form two products having an accurate mass of m/z 335.2228, corresponding to the mass of the ct-8,9-E-HET products, as has previously been observed to form with COX-1 (17). Structure assignment for both was done by MS/MS fragmentation.…”

Section: Resultsmentioning

confidence: 99%

“…Although EETs are primarily metabolized by sEH, a few studies have observed that the 5,6-EET and 8,9-EET are substrates for COX-1 (17,18) and COX-2 (19). The COX metabolites of EETs have largely undefined biological activity, yet Homma et al determined that the ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) metabolite is a renal vasoconstrictor and potent mitogen, approximately three orders of magnitude more potent than its parent, 8,.…”

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confidence: 99%

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Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Rand

Barnych

Morisseau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.omega-6 fatty acids | epoxyeicosatrienoic acids | metabolism | cyclooxygenase | angiogenesis A rachidonic acid (ARA) is an omega-6 fatty acid that is metabolized by three major classes of enzymes, cyclooxygenases (COXs), lipoxygenases, and cytochrome P450s (CYPs), to produce an array of biologically active metabolites (1-3). The CYP pathway transforms ARA into four epoxyeicosatrienoic acids (EETs) in addition to hydroxylated metabolites (1). EETs have several biological actions, and are considered antihypertensive, antiinflammatory, neuroprotective, cardioprotective, and analgesic (4). EETs also play a role in angiogenesis (5-10), the formation of new blood vessels from preexisting vessels that is important for many physiological and pathological processes, including cancer (11).EETs can enhance tumor growth and metastasis through their angiogenic activity (12); however, this activity is transient due to their metabolic instability. EETs are further metabolized by epoxide hydrolases (EHs), primarily soluble epoxide hydrolase (sEH), to their corresponding diols (4, 13), which are generally not biologically active (14) (Fig. 1A). Inhibition of sEH prolongs EET biological activity, potentiating their angiogenic activity, leading to increased tumor growth and metastasis in some systems (12, 15) (Fig. 1B).ARA can also be metabolized by COX to form proangiogenic and proinflammator...

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Rand

Barnych

Morisseau

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…5,6-EET is converted to a prostaglandin analog, 5,6-epoxyprostaglandin (PG) E 1 , which functions as a renal vasodilator (12). 8(S),9(R)-EET can undergo only a partial cyclooxygenase reaction and is converted to 11-hydroxy-8,9-EET, a renal vasoconstrictor and mitogen for glomerular mesangial cells (73,178).…”

Section: Eet Metabolismmentioning

confidence: 99%

Action of epoxyeicosatrienoic acids on cellular function

Spector

Norris²

2007

American Journal of Physiology-Cell Physiology

415

450

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Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca2+-activated K+ channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney. Many of the functional effects of EETs occur through activation of signal transduction pathways and modulation of gene expression, events probably initiated by binding to a putative cell surface EET receptor. However, EETs are rapidly taken up by cells and are incorporated into and released from phospholipids, suggesting that some functional effects may occur through a direct interaction between the EET and an intracellular effector system. In this regard, EETs and several of their metabolites activate peroxisome proliferator-activated receptor α (PPARα) and PPARγ, suggesting that some functional effects may result from PPAR activation. EETs are metabolized primarily by conversion to dihydroxyeicosatrienoic acids (DHETs), a reaction catalyzed by soluble epoxide hydrolase (sEH). Many potentially beneficial actions of EETs are attenuated upon conversion to DHETs, which do not appear to be essential under routine conditions. Therefore, sEH is considered a potential therapeutic target for enhancing the beneficial functions of EETs.

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Hydroxylation and Dihydroxylation

Holland¹

1998

Biotechnology

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Regiospecific and enantioselective metabolism of 8,9-epoxyeicosatrienoic acid by cyclooxygenase

Cited by 40 publications

References 20 publications

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Action of epoxyeicosatrienoic acids on cellular function

Hydroxylation and Dihydroxylation

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