Epoxyeicosatetraenoic acid

Epoxyeicosatetraenoic acids (EEQs or EpETEs) are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

EPA is a straight-chain, 20 carbon omega-3 fatty acid containing cis (see Cis–trans isomerism) double bounds between carbons 5 and 6, 8 and 9, 11 and 12, 14 and 15, and 17 and 18; each of these double bonds is designated with the notation Z to indicate its cis configuration in the IUPAC Chemical nomenclature used here. EPA is therefore 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid. Certain cytochrome P450 epoxygenases metabolize EPA by converting one of these double bounds to an epoxide thereby forming one of 5 possible eicosatetraenoic acid epoxide regioisomers (see Structural isomer, section on position isomerism (regioisomerism)). These regioisomers are: 5,6-EEQ (i.e. 5,6-epoxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid), 8,9-EEQ (i.e. 8,9-epoxy-5Z,11Z,14Z,17Z-eicosatetraenoic acid), 11,12-EEQ (i.e. 11,12-epoxy-5Z,8Z,14Z,17Z-eicosatetraenoic acid), 14,15-EEQ (i.e. 14,15-epoxy-5Z,8Z,11Z,17Z-eicosatetraenoic acid, and 17,18-EEQ (i.e. 17,18-epoxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid. The epoxydases typically make both R/S enantiomers of each epoxide. For example, they metabolize EPA at its 17,18 double bond to a mixture of 17R,18S-EEQ and 17S,18R-EEQ. The EEQ products therefore consist of as many as 10 isomers.

Cellular cytochrome P450 epoxygenases metabolize various polyunsaturated fatty acids to epoxide-containng products. They metabolize the omega-6 fatty acids arachidonic acid, which possess four double bonds, to 8 different epoxide isomers which are termed epoxyeicosatrienoic acids or EETs and linoleic acid, which possess two double bonds, to 4 different epoxide isomers, i.e. two different 9,10-epoxide isomers termed vernolic acids or leukotoxins and two different 12,13-epoxides isomers termed coronaric acids or isoleukotoxins. They metabolize the omega-3 fatty acid, docosahexaenoic acid, which possesses 6 double bonds, to 12 different epoxydocosapentaenoic acid (EDPs) isomers. In general, the same epoxygenases that accomplish these metabolic conversions also metabolize the omega-6 fatty acid, EPA, to 10 epoxide isomers, the EEQs. These epoxygenases fall into several subfamilies including the cytochrome P4501A (i.e.CYP1A), CYP2B, CYP2C, CYP2E, and CYP2J subfamilies, and within the CYP3A subfamily, CYP3A4. In humans, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, CYP3A4, and CYP2S1 metabolize EPA to EEQs, in most cases forming principally 17,18-EEQ with smaller amounts of 5,6-EEQ, 8,9-EEQ, 11,12-EEQ, and 14,15-EEQ isomers. However, CYP2C11, CYP2C18, and CYP2S1 also form 14,15-EEQ isomers while CYP2C19 also forms 11,12-EEQ isomers. The isomers formed by these CYPs vary greatly with, for example, the 17,18-EEQs made by CYP1A2 consisting of 17R,18S-EEQ but no detectable 17S,18R-EEQ and those made by CYP2D6 consisting principally of 17R,18S-EEQ with far smaller amounts of 17S,18R-EEQ. In addition to the cited CYP's, CYP4A11, CYP4F8, CYP4F12, CYP1A1, CYP1A2, and CYP2E1, which are classified as CYP monooxygenase rather than CYP epoxygeanses because they metablize arachidonic acid to monohydroxy eicosatetraenoic acid products (see 20-Hydroxyeicosatetraenoic acid), i.e. 19-hydroxyhydroxyeicosatetraenoic acid and/or 20-hydroxyeicosatetranoic acid, take on epoxygease activity in converting EPA primarily to 17,18-EEQ isomers (see epoxyeicosatrienoic acid). 5,6-EEQ isomers are generally either not formed or formed in undetectable amounts while 8,9-EEQ isomers are formed in relatively small amounts by the cited CYPs. The EET-forming CYP epoxygenases often metabolize EPA to EEQs (as well as DHA to EDPs) at rates that exceed their rates in metabolizing arachidonic acid to EETs; that is, EPA (and DHA) appear to be preferred over arachidonic acid as substrates for many CYP epoxygenases.

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