Poxytrins or dihydroxy-E,Z,E-polyunsaturated fatty acids (dihydroxy-E,Z,E-PUFAs) are PUFA metabolites that possess two hydroxyl residues and three in-series conjugated double bonds in an E,Z,E cis–trans configuration. Poxytrins, unlike isomers with three conjugated double bonds in a different geometry, have unique platelet-inhibiting properties. The critical E,Z,E configuration may be involved in controlling platelets, and could prove useful in treating human conditions and diseases that involve pathological platelet activation.
Types
editPoxytrins are metabolites of docosahexaenoic acid (DHA), arachidonic acid (AA), and α-linolenic acid (ALA). Poxytrins derived from AA are termed linotrins.[1]
| Trivial name | Formula | Precursor |
|---|---|---|
| protectin DX (PDX) | 10R,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid | DHA |
| 10R,17S-diHDHA | 10R,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid | DHA |
| 10S,17S-diHDHA | 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid | DHA |
| 7-epi-MaR1 | 7S,14S-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid | DHA |
| 8S,15S-diHETE | 8S,15S-dihydroxy-5Z,9E,11Z,13E-eicosatetraenoic acid | AA |
| linotrin-1 | 9R,16S-dihydroxy-10E,12Z,14E-octadecatrienoic acid | ALA |
| linotrin-2 | 9S,16S-dihydroxy-10E,12Z,14E-octadecatrienoic acid | ALA |
PDX
editProtectin DX (PDX) is perhaps the most prominent poxytrin. It is not to be confused with its isomer protectin D1 (PD1). PD1 is structurally identical to PDX except that its three conjugated double bonds 11E,13E,15Z have the E,E,Z configuration. PDX and PD1 both possess potent specialized pro-resolving mediator (SPM) anti-inflammatory activity, but only PDX inhibits human platelet aggregation responses.[2] PDX's anti-platelet activity is shared with various other dihydroxy-E,Z,E-PUFAs, but not with dihydroxy-PUFAs that have an E,E,E or E,E,Z configuration.[1][3]
Cells make PDX by metabolizing DHA by double oxygenation with a 15-lipoxygenase to form the 10R,17S-hydroxperoxy intermediate which is reduced its 10R,17S-hydroxyl product, PDX, probably by cytosolic glutathione peroxidase 1 (GPX1).[2] Serial metabolism by two different lipoxygenases or by a lipoxygenase and a cytochrome P45 on a 1Z,4Z,7Z-PUFA may also make a 1,7-dihydroxy 2E,4Z,6E product.
Other poxytrins
edit- 10R,17S-diHDHA is the 10R diastereomer of PDX, with the 10R hydroxyl residue being formed by aspirin-treated COX-2 or a cytochrome P450.
- 8S,15S-diHETE has been observed in Guinea pig tissues, probably made through double oxygenation of AA by a 15-lipoxygenase (probably ALOX15) or serial metabolism by two enzymes.[4]
- 10S,17S-diHDHA is the 13Z cis–trans isomer of 10-epi-protectin D (which has a 13E double bond instead). 10S,17S-diHDHA is formed in vitro by stimulated human leukocytes and possesses SPM anti-inflammatory activity.[5]
- 7-epi-MaR1 is a maresin isomer1, and likewise possesses SPM activity.[2]
Linotrins
editLinotrin-1 and linotrin-2 are among the four isomeric metabolites produced by incubating ALA with ALOX15B.[6] The extent to which the linotrins form in cells or in vitro is not clear.
Activity
editStimulating agents such as collagen depend on platelets to make and release thromboxane A2 (TXA2) to mediate and/or enhance their aggregating activity. 10R,17S-diHDHA, and PDX to a slightly lesser degree, inhibit the human platelet aggregation response to collagen at ≥ 100–200 nanomolar concentrations. This appears to reflect the ability of poxytrins to inhibit the activities of COX-1 and COX-2, thereby blocking the production of TXA2 and thus interfering with the activation of the thromboxane receptor by TXA2.[1][3] The linotrins appear to use a similar mechanism, and to have similar or slightly lower potencies.[1][6] However, the linotrins are 20- to 100-fold stronger in inhibiting human platelet aggregation compared to 5-HETE and 12-HETE, two mono-hydroxyl-containing eicosanoids that contain an E,Z conjugated double bond configuration.[7] Other biologically-active poxytrins have yet to be tested for, but are projected to possess anti-platelet activity.
References
edit- ^ a b c d Lagarde M, Véricel E, Liu M, Chen P, Guichardant M (2014). "Structure-function relationships of non-cyclic dioxygenase products from polyunsaturated fatty acids: poxytrins as a class of bioactive derivatives" (PDF). Biochimie. 107 Pt A: 91–4. doi:10.1016/j.biochi.2014.09.008. PMID 25223888. S2CID 31338779.
- ^ a b c Balas L, Guichardant M, Durand T, Lagarde M (2014). "Confusion between protectin D1 (PD1) and its isomer protectin DX (PDX). An overview on the dihydroxy-docosatrienes described to date". Biochimie. 99: 1–7. doi:10.1016/j.biochi.2013.11.006. PMID 24262603.
- ^ a b Chen P, Véricel E, Lagarde M, Guichardant M (2011). "Poxytrins, a class of oxygenated products from polyunsaturated fatty acids, potently inhibit blood platelet aggregation". FASEB Journal. 25 (1): 382–8. doi:10.1096/fj.10-161836. PMID 20833872. S2CID 21164301.
- ^ Sehmi R, Cromwell O, Taylor GW, Kay AB (1991). "Identification of guinea pig eosinophil chemotactic factor of anaphylaxis as leukotriene B4 and 8(S),15(S)-dihydroxy-5,9,11,13(Z,E,Z,E)-eicosatetraenoic acid". Journal of Immunology. 147 (7): 2276–83. doi:10.4049/jimmunol.147.7.2276. PMID 1655889. S2CID 19598067.
- ^ Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA (2006). "Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes". Journal of Immunology. 176 (3): 1848–59. doi:10.4049/jimmunol.176.3.1848. PMID 16424216.
- ^ a b Liu M, Chen P, Véricel E, Lelli M, Béguin L, Lagarde M, Guichardant M (2013). "Characterization and biological effects of di-hydroxylated compounds deriving from the lipoxygenation of ALA". Journal of Lipid Research. 54 (8): 2083–94. doi:10.1194/jlr.M035139. PMC 3708359. PMID 23740966.
- ^ Croset M, Lagarde M (1983). "Stereospecific inhibition of PGH2-induced platelet aggregation by lipoxygenase products of icosaenoic acids". Biochemical and Biophysical Research Communications. 112 (3): 878–83. doi:10.1016/0006-291x(83)91699-6. PMID 6405751.