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1.
Article in English | MEDLINE | ID: mdl-7540307

ABSTRACT

A new radiolabeled metabolite was released into the extracellular fluid by normal human skin fibroblasts that were labeled with [5,6,8,9,11,12,14,15-3H] arachidonic acid. This product continued to accumulate during a 24 h incubation, and its formation was not saturated at arachidonic acid concentrations up to 15 mumol/L. The compound, identified as hexadecatrienoic acid, was not produced by Zellweger fibroblasts which are deficient in peroxisomal fatty acid beta-oxidation. By contrast, radiolabeled hexadecatrienoic acid was produced by mutant fibroblasts having other peroxisomal defects, including X-linked adrenoleukodystrophy, adult Refsum's disease, and rhizomelic chondrodysplasia punctata. This radiolabeled metabolite also was produced by mutant fibroblasts that cannot oxidize long-chain fatty acids in the mitochondria. These results indicate that hexadecatrienoic acid is synthesized from arachidonic acid by peroxisomal beta-oxidation. The absence of this pathway may account for some of the biochemical and functional abnormalities that occur in Zellweger's syndrome.


Subject(s)
Arachidonic Acid/metabolism , Fatty Acids, Unsaturated/metabolism , Microbodies/metabolism , Adrenoleukodystrophy/metabolism , Cells, Cultured , Chondrodysplasia Punctata/metabolism , Fatty Acids/metabolism , Fibroblasts/metabolism , Humans , Mitochondria/metabolism , Oxidation-Reduction , Refsum Disease/metabolism , Time Factors , Zellweger Syndrome/metabolism
2.
J Biol Chem ; 269(6): 4103-9, 1994 Feb 11.
Article in English | MEDLINE | ID: mdl-8307970

ABSTRACT

Human skin fibroblasts labeled with [5,6,8,9,11,12,-14,15-3H]arachidonic acid produce a radioactive metabolite that has a shorter retention time on reverse-phase high-performance liquid chromatography than arachidonic acid. This product is not retained in the cells; it is released entirely into the extracellular fluid in a time-dependent manner. The metabolite does not cochromatograph with any of the eicosanoid standards, and its formation is not prevented by the addition of cyclooxygenase, lipoxygenase, or cytochrome P-450 inhibitors. The compound is not produced by fibroblasts labeled with [1-14C]arachidonic acid, suggesting that it is formed through an oxidative process. Chemical analyses indicated that the metabolite is 4,7,10-hexadecatrienoic acid (16:3). Peroxisome-deficient human skin fibroblasts did not produce 16:3, indicating that it probably is formed through peroxisomal beta-oxidation. Human umbilical vein endothelial cells and porcine pulmonary artery smooth muscle cells also release radioactive 16:3 following labeling with [3H]arachidonic acid. Therefore, the production of this metabolite is not limited only to fibroblasts. The fact that 16:3 is released into the extra-cellular fluid suggests that it may be a new type of lipid mediator derived from arachidonic acid, formed through a peroxisome-dependent oxidative process.


Subject(s)
Arachidonic Acid/metabolism , Microbodies/metabolism , Skin/metabolism , Animals , Cattle , Cells, Cultured , Chickens , Gas Chromatography-Mass Spectrometry , Humans , In Vitro Techniques , Skin/cytology , Species Specificity , Zellweger Syndrome/metabolism
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