Lipoic acid favors thiolsulfinate formation after hypochlorous acid scavenging: a study with lipoic acid derivatives.
Lipoic acid, the oxidized form of 6,8-dimercapto-octanoic acid has a strained cyclic disulfide in a 1,2-dithiolane ring. Recently its antioxidant activity gained attention. Hypochlorous acid (HOCl) is an oxidant produced by neutrophils. A prominent effect of HOCl is the inactivation of alpha-1-antiproteinase. Due to this inactivation, the ability of alpha-1-antiproteinase to inhibit elastase is lost. The resulting higher activity of elastase is held responsible for tissue damage in lung emphysema. We studied the HOCl scavenging capability of three metabolites of lipoic acid: tetranor-, bisnor-, and beta-lipoic acid. To obtain some insight on the molecular basis of HOCl scavenging 1,2-dithiane-4,5-diol, cystine, lipoic acid methyl ester, and lipoamide were also included in the study. The extent of alpha-1-antiproteinase inactivation by HOCl in the presence of scavenger was taken as a parameter to quantify the scavenging activity. It was found that lipoic acid, tetranor- and bisnorlipoic acid, lipoic acid methyl ester, and lipoamide all showed the same activity toward HOCl. beta-Lipoic acid, 1,2-dithiane-4,5-diol and cystine were less active. The products of lipoic acid after reaction with HOCl were studied using GC/MS. Indications for thiolsulfinate formation were found by comparing these products with the GC/MS profile of beta-lipoic acid. Thiolsulfinate formation may also be suggested in the reaction of tetranor- and bisnorlipoic acid and lipoic acid methyl ester with HOCl. The present results show an antioxidant activity of the metabolites tetranor- and bisnorlipoic acid. The 1,2-dithiolane ring may enhance the reactivity toward HOCl compared to less strained disulfides, resulting in the formation a thiolsulfinate.
Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, The Netherlands.
G
G
Biewenga
J
J
de Jong
A
A
Bast
D016166:Free Radical Scavengers; D006997:Hypochlorous Acid / Q000737:chemistry* / Q000494:pharmacology; D019272:Leukocyte Elastase; D013058:Mass Spectrometry; D010196:Pancreatic Elastase / Q000187:drug effects; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology; D008063:Thioctic Acid / Q000737:chemistry* / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000187:drug effects
D016166:Free Radical Scavengers; D013451:Sulfonic Acids; D000515:alpha 1-Antitrypsin; C037741:alpha 1-antitrypsin-leukocyte elastase complex; D006997:Hypochlorous Acid; D008063:Thioctic Acid; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase