Structure-activity relationship for potentiation of EGF-dependent mitogenesis by oxygenated metabolites of linoleic acid.
Epidermal growth factor induces the oxygenation of linoleic acid in Syrian hamster embryo fibroblasts, and the lipoxygenase-derived products potentiate the mitogenic signal. We have further characterized the linoleate metabolites of growth factor-activated cells by chiral phase HPLC analysis. The primary product was identified as the pure (S) enantiomer of 13-hydroxyoctadecadienoic acid (HODE). In comparison to 13(R)-HODE isomer, only the biologically derived 13(S)-HODE was active in augmenting DNA synthesis as assessed by [3H]thymidine incorporation. To extend these investigations, we defined the structural requirements of analogous lipid compounds necessary for stimulation of mitogenesis in these cells. Carbon-chain length, degree of unsaturation, type of oxidized functionality, position of oxygenated moiety, double-bond geometry, and chirality were all identified as factors that modulate the mitogenic activity of related compounds. The results demonstrate a high degree of specificity for (S)-isomer hydro(pero)xylinoleic acid metabolites in stimulating DNA synthesis and further define the relationship between linoleic acid metabolism and growth-factor-dependent cell growth.
Glasgow
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Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
Eling
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D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D008647:Mesocricetus; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D008041:Linoleic Acids; D014316:Tritium; C024348:13-hydroxy-9,11-octadecadienoic acid; D004815:Epidermal Growth Factor; D004247:DNA; D019787:Linoleic Acid; D013936:Thymidine