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Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: an Emerging Therapeutic Target

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Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: an Emerging Therapeutic Target pharmaceutics Review Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: An Emerging Therapeutic Target Osama H. Elshenawy 1, Sherif M. Shoieb 1, Anwar Mohamed 1,2 and Ayman O.S. El-Kadi 1,* 1 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; [email protected] (O.H.E.); [email protected] (S.M.S.); [email protected] (A.M.) 2 Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates * Correspondence: [email protected]; Tel.: 780-492-3071; Fax: 780-492-1217 Academic Editor: Kishor M. Wasan Received: 12 January 2017; Accepted: 15 February 2017; Published: 20 February 2017 Abstract: Cytochrome P450-mediated metabolism of arachidonic acid (AA) is an important pathway for the formation of eicosanoids. The !-hydroxylation of AA generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in various tissues. In the current review, we discussed the role of 20-HETE in the kidney, liver, lung, and brain during physiological and pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal ischemia/reperfusion (I/R) injury and polycystic kidney diseases. The role of 20-HETE in the liver is not clearly understood although it represents 50%–75% of liver CYP-dependent AA metabolism, and it is associated with liver cirrhotic ascites. In the respiratory system, 20-HETE plays a role in pulmonary cell survival, pulmonary vascular tone and tone of the airways. As for the brain, 20-HETE is involved in cerebral I/R injury. Moreover, 20-HETE has angiogenic and mitogenic properties and thus helps in tumor promotion. Several inhibitors and inducers of the synthesis of 20-HETE as well as 20-HETE analogues and antagonists are recently available and could be promising therapeutic options for the treatment of many disease states in the future. Keywords: 20-hydroxyeicosatetraenoic acid (20-HETE); Cytochrome P450s (CYPs); arachidonic acid (AA); kidney; ischemia/reperfusion (I/R) injury; liver; lung; brain 1. Introduction Arachidonic acid (AA), which is a major component of cell membrane, is known to be metabolized into different classes of eicosanoids, by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP). COX is known to be responsible for production of prostaglandins (PGs); whereas LOX produces mid chain hydroxyeicosatetraenoic acids (HETEs), lipoxins (LXs), and leukotrienes (LTs). CYP enzymes produce epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and HETEs (terminal, sub-terminal, and mid-chain) by CYP hydroxylases [1–4]. Terminal hydroxylation of AA is known as !-hydroxylation reaction in which AA is converted to 20-HETE through CYP4A and CYP4F enzymes [5–7]. COX plays an important role in metabolism of 20-HETE providing a diverse range of activities in different organs [8]. 20-HETE is metabolized by COX into hydroxyl analogue of vasoconstrictor prostaglandin H2 (20-OH PGH2) which is further transformed by isomerases into vasodilator/diuretic metabolites (20-OH PGE2, 20-OH PGI2) and vasoconstrictor/antidiuretic metabolites (20-OH Thromboxane A2, 20-OH PGF2a)[9–11]. Pharmaceutics 2017, 9, 9; doi:10.3390/pharmaceutics9010009 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2017, 9, 9 2 of 28 A numberPharmaceutics of selective2017, 9, 9 inhibitors for 20-HETE synthesis have been previously used including2 of 28 17-octadecynoic acid (17-ODYA), N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), 44 selective inhibitors for 20-HETE synthesis have been previously used including 17-octadecynoic acid dibromododec-11-enoicPharmaceutics 2017, 9, 9 acid (DBDD), N-hydroxy-N’-(4-butyl-2methylphenyl)formamidine (HET0016),2 of 28 45 (17-ODYA), N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), dibromododec-11-enoic N-(3-Chloro-4-morpholin-4-yl)Phenyl-N’-hydroxyimido formamide (TS011) and acetylenic fatty acid 4446 selectiveacid (DBDD), inhibitors N -hydroxy-for 20-HETEN’-(4-butyl-2methylphenyl)formamidine synthesis have been previously used includ (HET0016),ing 17-octadecynoic N-(3-Chloro-4- acid sodium 10-undecynyl sulfate (10-SUYS) [5,6,12–16]. Nonselective inhibitors of AA metabolism were 4547 (17-ODYA),morpholin-4-yl)Phenyl- N-methylsulfonyl-12,12-dibromododec-11-N’-hydroxyimido formamide (TS011)enamide and (DDMS), acetylenic dibromododec-11-enoic fatty acid sodium 10- 4648also usedacidundecynyl including(DBDD), sulfate 1-AminobenzotriazoleN (10-SUYS)-hydroxy-N’ [5,6,1-(4-butyl-2methylphenyl)formamidine2–16]. Nonselective (ABT) and inhibitors Cobalt (II) of chlorideAA (HET0016),metabolism (CoCl 2wereN)[-(3-Chloro-4-17 ,also18]. used Recently, 4749competitive morpholin-4-yl)Phenyl-including antagonists 1-Aminobenzotriazole haveN’-hydroxyimido been (ABT employed) and formamide Cobalt including (II) (TS011)chloride 20-hydroxyeicosa-6(Z),15(Z)-dienoic and (CoCl acetylenic2) [17,18]. fatty Recently, acid competitivesodium 10- acid 4850(6,15,20-HEDE; undecynylantagonists sulfate WIT002)have been (10-SUYS) and employed 20-hydroxyeicosa-6(Z),15(Z)-dienoyl]glycine [5,6,1 including2–16]. Nonselective 20-hydroxyeicosa-6(Z),15(Z)-dienoic inhibitors of AA metabolism (6,15,20-HEDGE) acid (6,15,20-HEDE;were also used[5,13 –15]. 4951Peroxisome includingWIT002) proliferator-activatedand 1-Aminobenzotriazole 20-hydroxyeicosa-6(Z),15(Z)-dienoyl]glycine (ABT receptor) and Cobalt alpha (II) (PPAR chloride (6,15,20-HEDGE)α) (CoCl agonists,2) [17,18]. such [5,13–15].Recently, as fenofibrate competitivePeroxisome and 5052clofibrate, antagonistsproliferator-activated or gene have therapy been receptoremployed were alpha usedincluding (PPAR to upregulate 20-hydroα) agonists,xyeicosa-6(Z),15(Z)-dienoic the such formation as fenofibrate of 20-HETE and acid clofibrate, (6,15,20-HEDE; besides or 20-HETEgene 5153mimetics, WIT002)therapy 20-hydroxyeicosa-5(Z),14(Z)-dienoic wereand 20-hydroxyeicosa-6(Z),15(Z)-dienoyl]glycineused to upregulate the formatio acid (5,14,20-HEDE;n of 20-HETE (6,15,20-HEDGE) besides WIT003), 20-HETE and[5,13–15].N-[20-hydroxyeicosa- mimetics, Peroxisome 20- 5254 hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14,20-HEDE; WIT003), and N-[20-hydroxyeicosa- 5(Z),14(Z)-dienoyl]glycineproliferator-activated receptor (5,14,20-HEDGE) alpha (PPAR [13α), 15agonists,] (Figure such1 represents as fenofibrate a summarization and clofibrate, for or 20-HETEgene 5355 therapy5(Z),14(Z)-dienoyl]glycine were used to upregulate (5,14,20-HEDGE) the formatio [13,15]n of(Figure 20-HETE 1 represents besides a20-HETE summarization mimetics, for 20- modulators commonly used in previous literature). 5456 hydroxyeicosa-5(Z),14(Z)-dienoicHETE modulators commonly used inacid previous (5,14,20-HEDE; literature). WIT003), and N-[20-hydroxyeicosa- 55 5(Z),14(Z)-dienoyl]glycine (5,14,20-HEDGE) [13,15] (Figure 1 represents a summarization for 20- 56 HETE modulators commonly used in previous literature). 57 58 Figure 1. Different 20-hydroxyeicosatetraenoic acid (20-HETE) modulators commonly used to study the Figure 1. Different 20-hydroxyeicosatetraenoic acid (20-HETE) modulators commonly used to study 5759 role of 20-HETE in vivo and in vitro. the role of 20-HETE in vivo and in vitro. 58 Figure 1. Different 20-hydroxyeicosatetraenoic acid (20-HETE) modulators commonly used to study the 5960 roleNotably, of 20-HETE eicosanoids in vivo and exert in vitro.their action through specific receptors called eicosanoid receptors, in 61 Notably,addition to eicosanoids non-specific exert receptors their such action as throughPPAR receptors specific [19]. receptors Recent called data demonstrated eicosanoid receptors, the 6062in additionidentificationNotably, to non-specific eicosanoidsof a novel receptorsGexert protein-coupled their suchaction asthrough receptor PPAR sp receptors(GPCR)ecific receptors as [ 1920-HETE]. called Recent receptor eico datasanoid in demonstrated receptors,the vascular in the 6163identification additionendothelium to of non-specific a[20]. novel The Gidentification protein-coupledreceptors such of 20-HETE as receptorPPAR receptor receptors (GPCR) would [19]. as result 20-HETERecent in betterdata receptor demonstratedunderstanding in the vascularthe of 64 molecular mechanisms and clinical implications of 20-HETE in different organs. In this review, 20- 62endothelium identification [20]. of The a novel identification G protein-coupled of 20-HETE receptor receptor (GPCR) would as 20-HETE result inreceptor better in understanding the vascular of 6365 endotheliumHETE role in[20]. the The kidney, identification liver, oflung 20-HETE and brainreceptor during would normal result inphysiology, better understanding and during of molecular mechanisms and clinical implications of 20-HETE in different organs. In this review, 20-HETE 6466 molecularpathophysiological mechanisms disease and states clinical will implications be discussed of (summarized20-HETE in different in Figure organs. 2). In this review, 20- role in the kidney, liver, lung and brain during normal physiology, and during pathophysiological 65 HETE role in the kidney, liver, lung and brain during normal physiology, and during 66disease pathophysiological states will be discussed disease states (summarized will be discussed in Figure (summarized2). in Figure 2). 67 68 Figure 2. Role of 20-HETE in the
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