Dihydrolipoic acid inhibits 15-lipoxygenase-dependent lipid peroxidation

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• 作者：Lapenna ; Domenico ; Ciofani ; Giuliano ; Pierdomenico ; Sante Donato ; Giamberardino ; Maria Adele ; et. al.
• 关键词：Lipoic acid ; Dihydrolipoic acid ; 15-Lipoxygenase ; Lipid peroxidation ; Iron ; Free radicals ; Antioxidant ; Atherosclerosis ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2003
• 出版时间：November 15, 2003
• 年：2003
• 卷：35
• 期：10
• 页码：1203-1209
• 全文大小：94.4 K

文摘

The potential antioxidant effects of the hydrophobic therapeutic agent lipoic acid (LA) and of its reduced form dihydrolipoic acid (DHLA) on the peroxidation of either linoleic acid or human non-HDL fraction catalyzed by soybean 15-lipoxygenase (SLO) and rabbit reticulocyte 15-lipoxygenase (RR15-LOX) were investigated. DHLA, but not LA, did inhibit SLO-dependent lipid peroxidation, showing an IC₅₀ of 15 μM with linoleic acid and 5 μM with the non-HDL fraction. In specific experiments performed with linoleic acid, inhibition of SLO activity by DHLA was irreversible and of a complete, noncompetitive type. In comparison with DHLA, the well-known lipoxygenase inhibitor nordihydroguaiaretic acid and the nonspecific iron reductant sodium dithionite inhibited SLO-dependent linoleic acid peroxidation with an IC₅₀ of 4 and 100 μM, respectively, while the hydrophilic thiol N-acetylcysteine, albeit possessing iron-reducing and radical-scavenging properties, was ineffective. Remarkably, DHLA, but not LA, was also able to inhibit the peroxidation of linoleic acid and of the non-HDL fraction catalyzed by RR15-LOX with an IC₅₀ of, respectively, 10 and 5 μM. Finally, DHLA, but once again not LA, could readily reduce simple ferric ions and scavenge efficiently the stable free radical 1,1-diphenyl-2-pycrylhydrazyl in ethanol; DHLA was considerably less effective against 2,2′-azobis(2-amidinopropane) dihydrochloride-mediated, peroxyl radical-induced non-HDL peroxidation, showing an IC₅₀ of 850 μM. Thus, DHLA, at therapeutically relevant concentrations, can counteract 15-lipoxygenase-dependent lipid peroxidation; this antioxidant effect may stem primarily from reduction of the active ferric 15-lipoxygenase form to the inactive ferrous state after DHLA-enzyme hydrophobic interaction and, possibly, from scavenging of fatty acid peroxyl radicals formed during lipoperoxidative processes. Inhibition of 15-lipoxygenase oxidative activity by DHLA could occur in the clinical setting, eventually resulting in specific antioxidant and antiatherogenic effects.