Free radical oxidation of 15-(S)-hydroxyeicosatetraenoic acid with the Fenton reagent: characterization of an epoxy-alcohol and cytotoxic 4-hydroxy-2E-nonenal from the heptatrienyl radical pathway.
The oxidation of (5Z,8Z,11Z,13E,15S)-15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-(S)-HETE, 1a) with the Fenton reagent (Fe2+/EDTA/H2O2) was investigated. In phosphate buffer, pH 7.4, the reaction proceeded with 75% substrate consumption after 1 h to give a mixture of products, one of which was identified as (2E,4S)-4-hydroxy-2-nonenal (3a, 18% yield). Methylation of the mixture with diazomethane allowed isolation of another main product which could be identified as methyl (5Z,8Z,13E)-11,12-trans-epoxy-15-hydroxy-5,8,13-eicosatrienoate (2a methyl ester, 8% yield). A similar oxidation carried out on (15-(2)H)-15-HETE (1b) indicated complete retention of the label in 2b methyl ester and 3b, consistent with an oxidation pathway involving as the primary event H-atom abstraction at C-10. Overall, these results support the recently proposed role of 1a as a potential precursor of the cytotoxic gamma-hydroxyalkenal 3a and disclose a hitherto unrecognized interconnection between 1a and the epoxy-alcohol 2a, previously implicated only in the metabolic transformations of the 15-hydroperoxy derivative of arachidonic acid.
Manini
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Department of Organic Chemistry and Biochemistry, University of Naples Federico II, Via Cinthia 4, I-80126 Naples, Italy.
Briganti
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Fabbri
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Picardo
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Napolitano
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d'Ischia
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D000447:Aldehydes / Q000737:chemistry* / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000633:toxicity; D003903:Deuterium / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D015525:Fatty Acids, Omega-3 / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry*; D007501:Iron / Q000737:chemistry*; D007553:Isotope Labeling; D015227:Lipid Peroxidation; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008956:Models, Chemical; D010084:Oxidation-Reduction; D013237:Stereoisomerism
D000447:Aldehydes; D003432:Cross-Linking Reagents; D004852:Epoxy Compounds; D015525:Fatty Acids, Omega-3; C045076:Fenton's reagent; D005609:Free Radicals; D006893:Hydroxyeicosatetraenoic Acids; C102870:trienyl; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D003903:Deuterium; D006861:Hydrogen Peroxide; D007501:Iron; C027576:4-hydroxy-2-nonenal