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J. Biol. Chem., Vol. 276, Issue 39, 36059-36062, September 28, 2001

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MINIREVIEW
Epoxygenase Pathways of Arachidonic Acid Metabolism^*

Darryl C. Zeldin

From the Division of Intramural Research, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

	INTRODUCTION

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

Arachidonic acid (AA)¹ is present in vivo esterified to cell membrane glycerophospholipids. Activation of phospholipases (e.g. cytosolic phospholipase A₂) releases free AA from the phospholipid (PL) pools and makes it available for oxidative metabolism by several enzyme systems (Fig. 1). The prostaglandin endoperoxide H synthases (PGHSs) metabolize AA to PGH₂, which serves as the precursor of the prostaglandins, thromboxane and prostacyclin (1). The lipoxygenases (LOXs) convert AA to labile hydroperoxy intermediates that go on to form the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins (2). The PGHSs and LOXs have been extensively studied, and their eicosanoid products have been shown to play important functional roles in a variety of fundamental biological processes such as inflammation, cellular proliferation, and intracellular signaling (1, 2). In contrast, less is known about the "third pathway" of AA metabolism wherein multiple cytochromes P450 metabolize AA to three types of eicosanoid products (3-6). Allylic oxidation forms several midchain conjugated dienols (5-, 8-, 9-, 11-, 12-, and 15-HETEs). -terminal hydroxylation forms C₁₆-C₂₀ alcohols of AA (16-, 17-, 18-, 19-, and 20-HETEs). Olefin epoxidation (also called the epoxygenase reaction) results in the production of four cis-epoxyeicosatrienoic acids (14,15-, 11,12-, 8,9-, and 5,6-EETs), each of which can be formed as either the R,S or the S,R enantiomer (Fig. 2). Studies have demonstrated that P450 epoxygenase-derived eicosanoids have a multitude of potent biological activities. For example, EETs have been shown to have potent effects on peptide hormone secretion (7-9), vascular and bronchial smooth muscle tone (10-15), and ionic transport (16-18). The EETs have also been shown to play critical roles in regulating cellular proliferation (16, 19, 20), inflammation (21), hemostasis (22), and a variety of intracellular signaling pathways (19, 23-27). This minireview will provide a general overview of the AA epoxygenase pathway with emphasis on the P450 enzymes involved in EET biosynthesis, the metabolic fate of the EETs once they are formed, and the biological relevance of the EETs in the kidney and cardiovascular system.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   The eicosanoid biosynthetic pathway. In response to hormonal stimulation, phospholipases are activated to release AA from membrane PLs. Free arachidonate is then metabolized along one of three pathways. The PGHSs metabolize AA to prostaglandins, thromboxane and prostacyclin. The LOXs metabolize AA to leukotrienes, HETEs and lipoxins. The P450 monooxygenases metabolize AA to midchain HETEs, -terminal HETEs, and the EETs. The products of the epoxygenase reaction possess a myriad of important biological effects in various tissues.

View larger version (21K): [in this window] [in a new window]   Fig. 2.   EET stereoisomers. Each of the four EET regioisomers can be biosynthesized as either the R,S or the S,R enantiomer.

	Biosynthesis of the EETs by Cytochrome P450s

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

Studies using purified and/or recombinant P450 enzymes have demonstrated that multiple P450s can metabolize AA to EETs, albeit with different catalytic efficiencies. Thus, members of the mammalian CYP1A, CYP2B, CYP2C, CYP2D, CYP2G, CYP2J, CYP2N, and CYP4A subfamilies have been shown to be capable of EET biosynthesis in vitro (28-36). In general, the regioselectivity of EET formation is P450 isoform-specific. For example, CYP2C8 forms 14,15-EET and 11,12-EET in a ratio of 1.3:1.0 but does not produce significant amounts of 8,9-EET. In contrast, CYP2C9, which is >80% identical to CYP2C8, produces 14,15-EET, 11,12-EET, and 8,9-EET in a ratio of 2.3:1.0:0.5 (30, 37). The stereoselectivity of EET biosynthesis also depends on the P450 isoform involved in catalysis. Thus, CYP2C8 produces (14R,15S)-EET and (11R,12S)-EET with optical purities of 86 and 81%, respectively. In contrast, CYP2C9 produces (14R,15S)-EET and (11S,12R)-EETs with significantly lower optical purities (63 and 69%, respectively) (30, 37). Multiple P450s may contribute to EET biosynthesis in a given tissue or cell type. Moreover, the contribution of an individual P450 isoform will depend on both its organ/cellular abundance and its catalytic efficiency. For example, in human and rat liver, CYP2C isoforms are highly expressed and likely contribute significantly to EET biosynthesis. Indeed, polyclonal antibodies to CYP2C isoforms inhibit >70% of hepatic microsomal AA epoxygenase activity (37-39). Similarly, in human and rat kidney, CYP2C isoforms are responsible for the majority of EET biosynthesis (30, 40). In contrast, in human and rat heart, CYP2J isoforms are particularly abundant and have been proposed to be the predominant enzymes responsible for epoxidation of endogenous AA pools (34, 41). Both CYP2J and CYP2C isoforms appear to contribute to EET biosynthesis in vascular endothelial cells, although their relative contribution remains unknown (21, 42-44). In most tissues, however, the relative contribution of different P450s to EET biosynthesis remains unknown due to the absence of P450 isoform-specific chemical inhibitors and inhibitory antibodies.

EET biosynthesis can be altered by factors that affect P450 expression and/or activity. Treatment of rats with phenobarbital induces CYP2B subfamily P450s leading to increased hepatic AA epoxygenase activity and altered regio- and stereochemical selectivity of rat liver EETs (35, 45). In contrast, treatment of rats with the aromatic hydrocarbon -naphthoflavone results in reduced hepatic AA epoxygenase activity and a concomitant increase in the formation of -terminal HETEs (35). The effects of aromatic hydrocarbons on P450 epoxygenase activity are species-dependent. Treatment of fish and avian species with benzo(a)pyrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin increases hepatic EET biosynthesis, likely by inducing CYP1A subfamily P450s (46, 47).

Nutritional factors can modulate P450-dependent AA metabolism. Fasting leads to reduced hepatic CYP2C11 expression and decreased epoxygenase activity in rats (48). EET biosynthesis is increased in vascular tissue isolated from rabbits fed a cholesterol-rich diet compared with control rabbits suggesting that dietary cholesterol alters P450 AA metabolism (49). Dietary salt has been shown to induce rat kidney CYP2C23 resulting in increased renal EET biosynthesis and enhanced urinary secretion of epoxygenase metabolites (40, 50, 51).

Genetic variation in human P450 genes is well described; however, little is known about the effect of P450 genetic polymorphism on AA metabolic pathways. A coding polymorphism in the human CYP2C8 gene (CYP2C8*3), which includes both R139K and K399R amino acid substitutions, has been shown to result in significantly reduced AA epoxygenase activity (52). We have recently identified several polymorphisms within the CYP2J2 gene that result in nonconservative amino acid substitutions that affect P450 enzyme function.² It is not yet known whether the frequency of these polymorphisms is altered in diseased patients.

	Metabolic Fate of the EETs

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

Once formed, the EETs can be further metabolized along a number of pathways as illustrated in Fig. 3. Capdevila and co-workers (53, 54) have documented the presence of glycerophospholipids that contain an epoxyeicosatrienoate moiety esterified to the glycerol-sn-2 position. These novel EET-PLs are formed in vivo by a multienzyme process initiated by P450 epoxidation of AA followed by ATP-dependent activation to epoxyeicosatrienoyl-CoA derivatives and finally regio- and stereoselective lysolipid acylation (54). In fact, the majority (>85%) of endogenous EETs present in mammalian tissues are esterified to cellular glycerophospholipids. Importantly, it has recently been shown that 1-palmitoyl-2-epoxyeicosatrienoyl phosphatidylcholine significantly inhibits the activity of porcine L-type Ca²⁺ channels reconstituted into planar lipid bilayers, suggesting that these EET-PLs may be involved in the regulation of membrane ion permeabilities (55).

View larger version (21K): [in this window] [in a new window]   Fig. 3.   Metabolic fate of the EETs. Once formed, the EETs can be metabolized along a number of different pathways. Lysolipid acylation results in the incorporation of EETs into cellular PLs. Epoxide hydration results in the formation of DHETs. Glutathione conjugation of EETs results in the biosynthesis of a series of glutathione conjugates. Further oxidation by PGHS and P450s results in the formation of epoxyprostaglandins, diepoxides, THF-diols, and epoxyalcohols. -oxidation results in the production of a series of chain-shortened fatty acids. Chain elongation converts EETs to 22-carbon fatty acid epoxides. Intracellular FABP may bind EETs, thus modulating their metabolism, activities, and/or targeting.

EETs can be hydrated to their corresponding vic-dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH) (56-59). The microsomal epoxide hydrolase can also metabolize EETs, albeit at significantly lower rates. The documentation of DHETs as endogenous constituents of liver, lung, and urine confirms that EET hydration occurs in vivo (15, 38, 60). The metabolism of EETs by sEH is highly regioselective with 14,15-EET being the preferred substrate. The hydration of 11,12-EET and 8,9-EET by sEH proceeds at significantly lower rates, and 5,6-EET is a very poor substrate for this enzyme (57). The metabolism of EETs by sEH is also highly stereoselective for the (14R,15S)-EET, (11S,12R)-EET, and (8S,9R)-EET enantiomers (57). Because DHETs are incorporated into PLs to a much lesser extent than EETs, Weintraub et al. (61) have postulated that sEH functionally regulates this process. Whereas the rapid conversion of EETs to their corresponding diols has generally been viewed as a process whereby EETs are rendered biologically inactive, DHETs have been shown to be vasoactive in the coronary circulation and are inhibitors of the hydroosmotic effect of arginine vasopressin in the kidney (62-64).

Incubations of EETs with rat or mouse liver microsomal P450 results in the production of a series of diepoxyeicosadienoic acids (diepoxides) and monohydroxyepoxyeicosatrienoic acids (epoxyalcohols) (59, 65). The diepoxides can be further metabolized by sEH to diol epoxides, which cyclize to the corresponding tetrahydrofuran-diols (THF-diols) (59). Little is known regarding the biological relevance of the diepoxides, epoxyalcohols, and THF-diols. Both 8,9-EET and 5,6-EET are substrates for PGHS (66-68). 5,6-EET is converted to both 5-hydroxy-PGI₁ and 5,6-epoxy-PGE₁ in rabbit kidney. Interestingly, the 5,6-epoxy-PGE₁ is equipotent to PGE₂ as a renal vasodilator whereas 5-hydroxy-PGI₁ is without activity (67). 8,9-EET is converted to 11-hydroxy-8,9-epoxyeicosatrienoic acid and 15-hydroxy-8,9-epoxyeicosatrienoic acid by PGHS. Importantly, the 11-hydroxy-8,9-epoxyeicosatrienoic acid has been shown to be a potent mitogen for rat glomerular mesangial cells (68). All four EETs can also serve as substrates for cytosolic glutathione S-transferase to form a series of glutathione conjugates, the biological relevance of which is unknown (69).

Fang et al. (62) have described several novel pathways of EET metabolism in endothelial cells. 11,12-EET is converted to 7,8-dihydroxy-18:2 via epoxide hydration and -oxidation. This compound possesses vasoactive properties in the coronary circulation. In the presence of epoxide hydrolase inhibition, these investigators observed the biosynthesis of the several chain-shortened -oxidation products including 10,11-epoxy-16:2, 7,8-epoxy-16:2, and 8,9-epoxy-14:1, as well as a chain elongation product 16,17-epoxy-22:3 (70).

Intracellular fatty acid-binding proteins (FABPs) may differentially bind EETs and DHETs, thus modulating their metabolism, activities, and/or targeting. Widstrom et al. (71) have recently evaluated the relative affinities of FABPs for several P450 epoxygenase-derived eicosanoids. The affinity of heart FABP for 5,6-EET and 11,12-EET (K_d ~0.4 µM) was ~20-fold greater than for DHETs (K_d ~8 µM). The homologous proteins, liver FABP and intestinal FABP, also displayed selective affinity for EETs versus DHETs. These investigators postulated that FABP binding of EETs may facilitate their intracellular retention whereas the lack of FABP affinity for DHETs may partially explain their release from cells.

	Biological Relevance of the EETs

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

The biological relevance of EETs and/or DHETs in various tissues has been the subject of a number of excellent reviews (3-6, 39, 72, 73). Herein, I will focus only on the role of these eicosanoids in kidney and cardiovascular function (summarized in Table I).

EETs are endogenous constituents of human and rodent kidney, and EET biosynthesis occurs throughout the nephron (74-77). Moreover, EETs have been shown to contribute to integrated renal function, either by directly affecting tubular transport processes, vascular tone, and cellular proliferation or by mediating the actions of renal hormones including renin, angiotensin II, and arginine vasopressin (3, 5, 6, 73). For example, in the proximal tubule, EETs inhibit Na⁺ transport and mediate the angiotensin II-induced rise in cytosolic Ca²⁺ (17, 78). In the collecting duct, P450 epoxygenase metabolites inhibit the hydroosmotic effect of arginine vasopressin, decrease net Na⁺ reabsorption and K⁺ secretion, and increase cytosolic Ca²⁺ concentrations (63, 79, 80). The EETs also have potent effects on renal vascular tone and are mitogenic in glomerular mesangial cells (12, 16, 75).

In addition to the well documented effects of EETs on renal vascular tone and fluid/electrolyte transport, several lines of evidence suggest that the P450 epoxygenase pathway may be involved in the pathogenesis of hypertension. First, the rat renal epoxygenases are under regulatory control by dietary salt, and their inhibition leads to the development of salt-dependent hypertension (40, 50, 51, 81). Second, spontaneously hypertensive rats have altered renal epoxygenase and epoxide hydrolase activities, and treatment of these animals with agents that either deplete renal P450 or inhibit sEH normalizes blood pressure (82-85). Third, the salt-sensitive phenotype in the Dahl rat model of genetic hypertension is associated with an inability to increase renal epoxygenase activity in response to dietary salt intake (81). Fourth, targeted disruption of the sEH gene lowers blood pressure in male mice in the absence and presence of dietary salt loading (86). Fifth, the urinary excretion of epoxygenase metabolites is profoundly increased in women with pregnancy-induced hypertension (60). Together these data suggest a role for P450 epoxygenases and sEH in blood pressure regulation and identify this pathway as an attractive target for therapeutic intervention.

EETs have been proposed to be endothelial derived hyperpolarizing factors (EDHFs) in that they relax vascular smooth muscle by opening large conductance, Ca²⁺-activated K⁺ channels (BK_Ca) in the smooth muscle cell membrane (10, 42, 87). Recent studies suggest that the mechanism by which EETs activate the BK_Ca channels involves ADP-ribosylation of the guanine nucleotide-binding protein G_S with a subsequent membrane-delimited action on the channel (88). Treatment of porcine coronary arteries with -naphthoflavone induces a CYP2C isoform, enhances EET biosynthesis, and increases EDHF-mediated hyperpolarization resulting in vasorelaxation (42). Moreover, transfection with an antisense oligonucleotide to CYP2C results in decreased CYP2C expression and attenuation of EDHF-mediated vascular responses, providing further evidence that the EDHF synthase in the porcine coronary vascular bed is a CYP2C isoform (42).

EETs have recently been shown to play important nonvasodilatory roles within the vasculature. Physiological concentrations (100 nM) of EETs or overexpression of human CYP2J2 decreased cytokine-induced endothelial cell adhesion molecule expression, and EETs prevented leukocyte adhesion to the vascular wall (21). The mechanism for the anti-inflammatory effect of the EETs was shown to involve inhibition of the transcription factor NF-B and IB kinase (21). In vascular endothelial cells, addition of EETs or overexpression of CYP2J2 increased tissue plasminogen activator (tPA) expression and fibrinolytic activity (22). Induction of tPA gene transcription by EETs was associated with increased G_S GTP-binding activity, increased intracellular cAMP levels, and cAMP-driven tPA promoter activation (22). Neither the anti-inflammatory effects nor the hemostatic actions of the EETs was blocked by BK_Ca channel inhibitors suggesting that these EET effects were independent of their membrane-hyperpolarizing actions (21, 22). Together these data suggest that EETs possess homeostatic properties in the vasculature in addition to their vasodilatory actions.

EETs have been shown to have effects on cardiomyocyte function. For example, 8,9-EET inhibits cardiac Na⁺ channels and produces a hyperpolarized shift in the steady-state membrane potential (89). Moffat et al. (90) demonstrated that both 5,6-EET and 11,12-EET significantly increase guinea pig cardiac myocyte cell shortening and intracellular calcium concentrations. Xiao et al. (91) showed that 11,12-EET enhanced L-type Ca²⁺ current and intracellular cAMP content in intact ventricular myocytes and that the P450 epoxygenase inhibitor clotrimazole suppressed cardiac myocyte cell shortening. In contrast, we have shown that 11,12-EET has direct inhibitory effects on cardiac L-type Ca²⁺ channels reconstituted into planar lipid bilayers suggesting that EETs can either increase or decrease Ca²⁺ channel activity depending on the metabolic and regulatory state of the cells (55). In an isolated-perfused rat heart model, 11,12-EET significantly improved recovery of heart contractile function following prolonged, global ischemia (41).

	Concluding Remarks

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

During the past two decades, the contributions of many laboratories have led to an improved understanding of the biochemical, pharmacological, and physiological relevance of the AA epoxygenase pathway. However, a number of important questions remain. Which specific P450 isoforms are primarily responsible for EET biosynthesis in various tissues? What are the signaling pathways and molecular mechanisms that underlie the biological actions of the EETs? What is the functional relevance of epoxygenase gene polymorphisms and are they associated with increased susceptibility to human disease? The application of modern molecular biological techniques such as gene overexpression and/or gene disruption, the development of specific P450 epoxygenase inhibitors and inhibitory antibodies, and the generation of stable EET receptor agonists/antagonists will facilitate future studies that attempt to address these and other critical questions.

	ACKNOWLEDGEMENTS

I am grateful to Drs. John R. Falck, William B. Campbell, and Jorge H. Capdevila for their helpful comments during the preparation of this manuscript. I apologize for omitting many relevant studies because of space constraints.

	FOOTNOTES

^* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.

To whom correspondence should be addressed: Laboratory of Pulmonary Pathobiology, NIEHS, National Institutes of Health, 111 T. W. Alexander Dr., Bldg. 101, Rm. D236, Research Triangle Park, NC 27709. Tel.: 919-541-1169; Fax: 919-541-4133; E-mail: zeldin@niehs.nih.gov.

Published, JBC Papers in Press, July 12, 2001, DOI 10.1074/jbc.R100030200

² L. King and D. C. Zeldin, unpublished data.

	ABBREVIATIONS

The abbreviations used are: AA, arachidonic acid; EET, cis-epoxyeicosatrienoic acid; DHET, dihydroxyeicosatrienoic acid; HETE, hydroxyeicosatetraenoic acid; sEH, soluble epoxide hydrolase; PGHS, prostaglandin H synthase; LOX, lipoxygenase; THF, tetrahydrofuran; PL, phospholipid; FABP, fatty acid-binding protein; EDHF, endothelial derived hyperpolarizing factor; tPA, tissue plasminogen activator.

	REFERENCES

TOP INTRODUCTION Biosynthesis of the EETs... Metabolic Fate of the... Biological Relevance of the... Concluding Remarks REFERENCES

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