title: Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals.
abstract: Thioctic (lipoic) acid is used as a therapeutic agent in a variety of diseases in which enhanced free radical peroxidation of membrane phospholipids has been shown to be a characteristic feature. It was suggested that the antioxidant properties of thioctic acid and its reduced form, dihydrolipoic acid, are at least in part responsible for the therapeutic potential. The reported results on the antioxidant efficiency of thioctic and dihydrolipoic acids obtained in oxidation models with complex multicomponent initiation systems are controversial. In the present work we used relatively simple oxidation systems to study the antioxidant effects of dihydrolipoic and thioctic acids based on their interactions with: (1) peroxyl radicals which are essential for the initiation of lipid peroxidation, (2) chromanoxyl radicals of vitamin E, and (3) ascorbyl radicals of vitamin C, the two major lipid- and water-soluble antioxidants, respectively. We demonstrated that: (1) dihydrolipoic acid (but not thioctic acid) was an efficient direct scavenger of peroxyl radicals generated in the aqueous phase by the water-soluble azoinitiator 2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile); (2) both dihydrolipoic acid and thioctic acid did not interact directly with chromanoxyl radicals of vitamin E (or its synthetic homologues) generated in liposomes or in the membranes by three different ways: UV-irradiation, peroxyl radicals of 2,2'-azobis(2,4-dimethylvaleronitrile), or peroxyl radicals of linolenic acid formed by the lipoxygenase-catalyzed oxidation; and (3) dihydrolipoic acid (but not thioctic acid) reduced ascorbyl radicals (and dehydroascorbate) generated in the course of ascorbate oxidation by chromanoxyl radicals. This interaction resulted in ascorbate-mediated dihydrolipoic acid-dependent reduction of the vitamin E chromanoxyl radicals, i.e. vitamin E recycling. We conclude that dihydrolipoic acid may act as a strong direct chain-breaking antioxidant and may enhance the antioxidant potency of other antioxidants (ascorbate and vitamin E) in both the aqueous and the hydrophobic membraneous phases.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley 94720.
authors.forename: V E
authors.initials: VE
authors.lastname: Kagan
authors.forename: A
authors.initials: A
authors.lastname: Shvedova
authors.forename: E
authors.initials: E
authors.lastname: Serbinova
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: C
authors.initials: C
authors.lastname: Swanson
authors.forename: R
authors.initials: R
authors.lastname: Powell
authors.forename: L
authors.initials: L
authors.lastname: Packer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry*; D001205:Ascorbic Acid / Q000737:chemistry*; D001391:Azo Compounds; D002839:Chromans / Q000737:chemistry; D005260:Female; D005609:Free Radicals; D007425:Intracellular Membranes / Q000737:chemistry* / Q000187:drug effects; D015227:Lipid Peroxidation; D008081:Liposomes / Q000737:chemistry*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009570:Nitriles; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001391:Azo Compounds; D002839:Chromans; D005609:Free Radicals; D008081:Liposomes; D009570:Nitriles; D010545:Peroxides; C055792:2,2'-azobis(2,4-dimethylvaleronitrile); D009243:NAD; C049375:perhydroxyl radical; D009249:NADP; D008063:Thioctic Acid; C015144:dihydrolipoic acid; D001205:Ascorbic Acid