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15-Hydroxyicosatetraenoic acid
15-Hydroxyicosatetraenoic acid (15-HETE, 15(''S'')-HETE, or 15''S''-HETE) is an endogenous eicosanoid, i.e. a metabolite of arachidonic acid. It is unambiguously designated by a shortened version of its IUPAC name as 15(''S'')-hydroxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid. ''S'' signifies the ''S'' chirality configuration of the compound's hydroxy residue, as distinguished from its 15(''R'')-hydroxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid, i.e. 15(''R'')-HETE or 15''R''-HETE, stereoisomer, while Z and E signify the cis–trans isomerism configurations, respectively, of its double bounds at carbon positions 5, 8, 11, and 13. Various cell types and tissues first produce 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(S)-HpETE), 15(''R'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acid (15(R)-HpETE), and/or a racemic mixture of both stereoisomers. These initial hydroperoxy products are extremely short lived in cells: if not otherwise metabolized, they are reduced to their 15(''S'')-HETE or 15(''R'')-HETE analogs. 15(''S'')-HpETE, 15(''R'')-HpETE, 15(''S'')-HETE, and 15(''R'')-HETE have stimulatory and inhibitory activities but often are further metabolized to a wide range of products that have activities which extend far beyond those of their precursors.〔Biochem, Pharm. 77:1-10,2009〕〔Cancer Metastasis 30:277-294, 2011〕〔J. Physiol. Sci. 62:163-172, 2012〕 Thus, the two hydroperoxy and two hydroxy metabolites have intrinsic activity but perhaps more importantly also flow into metabolizing pathways to form a larger number of more important biological products. The production and actions of these 15-hydroperoxy and 15-hydroxy eicosatetraenoates as well as those of their metabolites often differ greatly depending on cell-type or tissue-type studied.
== Production ==
Human tissues attack arachidonic acid with 15-lipoxygenase-1 (i.e., 15-LO-1, ALOX15) to form (15(''S'')-HpETE) as a major product and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',15''Z''-eicosatetraenoic acid and 14(''S''),15(''S'')-''trans''-oxido-5''Z'',8''Z'',11''Z''-14,15-leukotriene A4 as minor products; 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',15''Z''-eicosatetraenoic acids, i.e. 12-hydroperoxyicosatetraenoic acid (12-HpETE), are rapidly converted to 15(''S'')-HETE and 12(''S'')-hydroxy-5''Z'',8''Z'',10''E'',15''Z''-eicosatetraenoic acid (12-Hydroxyeicosatetraenoic acid), 12(''S'')-HETE), respectively, or flow into numerous other metabolic pathways while 14(''S''),15(''S'')-''trans''-oxido-5''Z'',8''Z'',11''Z''-14,15-leukotriene A4 is further metabolized by 15-LO-1 to various isomers of 8,15(''S'')-dihydroxy-5''S'',8''S'',''11Z'',13''S''-eicosatetraenoic acids, e.g. 8,15(S)-LTB4's.〔FEBS Letts. 60:149-152〕〔J. Biol. Chem 256:9483-9582, 1981〕〔J. Biol. Chem. 259, 14048-14053, 1984〕〔Amer. J. Physiol. 262:L392-L398, 1992〕〔Proc. Natl. Acad. Sci. USA 94: 6148-6152, 1997〕 Human 15-LOX-2 (i.e. ALOX15B) also makes 15(''S'')-HpETE and 15(''S'')-HETE but prefers linoleic acid over arachidonic acid as substrate and therefore produces 15(''S'')-HpETE and 15(''S'')-HETE as minor products; 15-LO-2 does not make 12-HETE.〔Proc. Natl. Acad. Sci. USA 94: 6148-6152, 1997〕 Human and rat microsomal cytochrome P450s, e.g. CYP2C19, metabolize arachidonic acid to a racemic mixture of 15-HETEs, i.e., 15(''R'',''S'')-HETEs, >90% of which is 15(''R'')-HETE.〔Biochim. Biophys. Acta 1166:258-263, 1993〕〔J. Pharmacol. Exp. Ther. 284:51-60, 1998〕 Human prostaglandin-endoperoxide synthase 1 (COX-1) and Prostaglandin-endoperoxide synthase 2 (COX-2) metabolize arachidonic acid primarily to prostaglandins but also to small amounts of 11(''R'')-HETE and a racemic mixture of 15-HETEs composed of ~22% 15(''R'')-HETE and 78% 15(''S'')-HETE.〔J. lipid Res. 51:575-585, 2010〕 When pretreated with aspirin, however, COX-1 is inactive while COX-2 attacks arachidonic acid to produce almost exclusively 15(''R'')-HETE along with its presumed precursor 15(''R'')-HpETE.〔Adv. Exp. Med. Biol. 447:133-149, 1999〕〔J. Biol. Chem. 275:6586-6591, 2000〕〔J. lipid Res. 51:575-585, 2010〕 The spontaneous and non-enzymatically-induced autooxidation of arachidonic acid yields 15(''R'',''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13''E''-eicosatetraenoic acids〔Prostaglandins 19:57-97, 1980〕〔Am. J. Pathol. 104:5-62, 1981〕 which in tissues would be rapidly converted to 15(''R'',''S'')-HETEs.
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