Original Article

Conversion of eicosapentaenoic acid to chain-shortened omega–3 fatty acid metabolites by peroxisomal oxidation

Correspondence to: Arthur A. Spector.

Human skin fibroblasts can convert arachidonic acid to 14- and 16-carbon polyunsaturated fatty acid products by peroxisomal ß-oxidation. The purpose of this study was to determine whether similar products are formed from eicosapentaenoic acid (EPA) and whether EPA and arachidonic acid compete for utilization by this oxidative pathway. Three radiolabeled metabolites with shorter retention times than EPA on reverse-phase high-performance liquid chromatography accumulated in the medium during incubation of fibroblasts with [5,6,8,9,11,12,14,15,17,18-³H] EPA ([³H]EPA). These metabolites, which were not formed from [1-¹⁴C]EPA and were not detected in the cells, were identified as tetradecatrienoic acid (14:3n–3), hexadecatetraenoic acid (16:4n–3), and octadecatetraenoic acid (18:4n–3). The most abundant product under all of the conditions tested was 16:4n–3. [³H]EPA was converted to 16:4n–3 and 14:3n–3 by fibroblasts deficient in mitochondrial long-chain acyl CoA dehydrogenase, but not by Zellweger syndrome or acyl CoA oxidase mutants that are deficient in peroxisomal ß-oxidation. Competition studies indicated that 16:4n–3 formation from 5 µM [³H]EPA was reduced by 60% when 10 µM arachidonic acid was added, but the conversion of [³H]arachidonic acid to its chain-shortened products was not decreased by the addition of 10 µM EPA.

These findings demonstrate that as in the case of arachidonic acid, chain-shortened polyunsaturated fatty acid products accumulate when EPA undergoes peroxisomal ß-oxidation. While EPA does not reduce arachidonic acid utilization by this pathway, it is possible that some biological actions of EPA may be mediated by the formation of the corresponding EPA products, 16:4n–3 and 14:3n–3.—Williard, D. E., T. L. Kaduce, S. D. Harmon, and A. A. Spector. Conversion of eicosapentaenoic acid to chain-shortened omega–3 fatty acid metabolites by peroxisomal oxidation. J. Lipid Res. 1998. 39: 978–986.

Supplementary key words: human skin fibroblasts, omega–3 fatty acids, hexadecatetraenoic acid, tetradecatrienoic acid, arachidonic acid, Zellweger syndrome, acyl CoA oxidase deficiency, long-chain acyl CoA dehydrogenase deficiency, hexadecatrienoic acid

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