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ACID
| Anusevicius ZJ;
Cenas NK: Dihydrolipoamide-mediated redox cycling of quinones.: Arch Biochem Biophys: 302:2:420-4 (1993) |
| The nonenzymatic reactions of dihydrolipoamide with a number of low-potential quinones, possessing either a fully or a partially substituted quinone ring at pH 7.0 were accompanied by consumption of oxygen in a significant excess of the quinone concentration, thus establishing their redox cycling. Contrary to this, only partially substituted quinones caused the consumption of oxygen in the presence of reduced glutathione due to reoxidation of reduced quinone- glutathione conjugates. Among compounds tested, 9,10- phenanthrene quinonecatalyzed the most rapid consumption of oxygen in the presence of dihydrolipoamide with subsequent formation of lipoamide and H2O2. The rate constant of anaerobic reduction of phenanthrene quinone by dihydrolipoamide was 8.6 +/- 1.6 x 10(3) M-1 s-1 (pH 7.0, 0.1 M phosphate, 20% ethanol, 25 degrees C). The consumption of oxygen and formation of lipoamide were inhibited by superoxide dismutase, indicating that the redox cycling involves the autooxidation of 9,10-dihydroxy phenanthrene, mediated by superoxide. The reaction was accompanied by the reduction of added cytochrome c, which was insignificantly inhibited by superoxide dismutase, and the reductive mobilization of iron from ferritin, activated by superoxide dismutase. These data raise the possibility that dihydrolipoamide, usually regarded as an antioxidant, under certain conditions may exert moderate prooxidant activity, initiating the formation of radicals and activated forms of oxygen. |
| A-2374 Biewenga G; de Jong J; Bast A: Lipoic acid favors thiolsulfinate formation after hypochlorous acid scavenging: a study with lipoic acid derivatives. Arch Biochem Biophys Jul: 312:1:114-20 (1994) |
| 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. |
| A-4756 Biewenga G; Haenen G; Bast A: The pharmacology of the antioxidant lipoic acid:Gen Pharmac: 29:3:315-31 (1997) |
| 1. Lipoic acid is an example of
an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA),formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by cheating Cd2+ 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy. |
| A-2367 Busse E; Zimmer G; Schopohl B; Kornhuber B: Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo.: Arzneimittelforschung Jun: 42:6:829-31 (1992) |
| The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole bodyirradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio. |
| A-2368 Kagan VE; Shvedova A; Serbinova E; Khan S; Swanson C; Powell R; Packer L: Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem Pharmacol Oct 20: 44:8:1637-49 (1992) |
| 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 azoinitiator2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator2,2'-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 Erecycling. 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. |
| A-4915 Koske D; Elstner EF: Coenzyme Q10, vitamin E and dihydrothioctic acid cooperatively prevent diene conjugation in isolated low density lipoprotein Boston: 1st Conf. of the Intl. Coenzyme Q10 Assn.: 119-120 (1998) |
| Lodge JK et al.: Natural sources
of lipoic acid: determination of lipollysine released from protease-digested tissues (1997) |
| A-2372 Packer L; Suzuki YJ:Vitamin E and alpha-lipoate: role in antioxidant recycling and activation of the NF-kappa Btranscription factor.: Mol Aspects Med: 14:3:229-39 (1993) |
| Nuclear factor kappa B (NF-kappa B) is believed to play an important role in the activation of human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS). Recent findings suggesting an involvement of reactive oxygen species in signal transduction pathways leading to NF-kappa Bactivation have encouraged the possible clinical use of antioxidants in blocking HIV activation. We have examined the effects of vitamin E and alpha-lipoate derivatives on NF-kappa B activation, and have observed that each of these antioxidants behave differently. Here we propose mechanisms of antioxidant actions ininfluencing cell signalling for NF-kappa B activation. |
| A-3237 Packer L; Witt EH; Tritschler HJ: alpha-Lipoic acid as a biological antioxidant. free Radic Biol Med: 19:2:227-50 (1995) |
| alpha-Lipoic acid, which plays an
essential role in mitochondrial dehydrogenase reactions, has recently gained considerable
attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with
reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid,
peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with
vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its
antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of
iron.alpha- Lipoic acid administration has been shown to be beneficial in a number of
oxidative stress models such as ischemia- reperfusion injury, diabetes (both alpha-lipoic
acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which
can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration,
and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins
such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review
the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions. |
| A-5002 Packer L: Alpha-lipoic acid: A metabolic antioxidant which regulates NF-KB signal transduction and protects against oxidative injury Drug Metabolism Reviews: 30:2:245-275 (1998) |
| Although the metabolic role of alpha-lipoic acid has been known for over 40 years, it is only recently that its effects when supplied exogenously have become known. Exogenous alpha-lipoic acid is reduced intracellularly by at least two and possibly three enzymes, and through the actions of its reduced form, it influences a number of cell processes. These include direct radical scavenging, recycling of other antioxidants, accelerating GSH synthesis, and modulating transcription factor activity, especially that of NF-kB. These mechanisms may account for the sometimes dramatic effects of alpha-lipoic acid in oxidative stress conditions (e.g. brain ischemia-reperfusion), and point the way toward its therapeutic use. |
| A-2375 Podda M; Tritschler HJ; Ulrich H; Packer L: Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency.: Biochem Biophys Res Commun: 204:1:98-104 (1994) |
| alpha-Lipoic acid, an essential cofactor in mitochondrial dehydrogenases, has recently been shown to be a potent antioxidant in vitro, as well as being capable of regenerating vitamin E in vitro. In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extraction of oxidized and reduced alpha-lipoic acid, we examined the antioxidant action of alpha-lipoic acid in vivo. Vitamin E-deficient adult hairless mice displayed obvious symptoms of deficiency within five weeks, but if the diet was supplemented with alpha-lipoic acid the animals were completely protected. At five weeks on a vitamin E-deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with alpha-lipoic acid: vitamin E levels in liver, kidney, heart, and skin decreased 70 to 85%; levels in brain decreased only 25%. These data show that there was no effect of alpha-lipoic acid supplementation on vitamin E tissue concentrations, arguing against a role for alpha-lipoic acid in regenerating vitamin E in vivo. |
| A-2373 Scott BC; Aruoma OI; Evans PJ; O'Neill C; Van der Vliet A; Cross CE; Tritschler H; Halliwell B:Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation.: Free Radic Res Feb: 20:2:119-33 (1994) |
| A detailed evaluation of the
antioxidant and pro-oxidant properties of lipoic acid (LA) and dihydrolipoic acid (DHLA)
was performed. Both compounds are powerful scavengers of hypochlorous acid, able to
protect alpha 1-antiproteinase against inactivation by HOCl. LA was a powerful scavenger
of hydroxyl radicals (OH.) and could inhibit both iron- dependent OH. generation and
peroxidation of ox-brain phospholipid liposomes in the presence of FeCl3-ascorbate,
presumably by binding iron ions and rendering them redox- inactive. By contrast,DHLA
accelerated iron-dependent OH. generation and lipid peroxidation, probably by reducing
Fe3+ to Fe2+. LA inhibited this pro-oxidant action of DHLA. However, DHLA did not
accelerate DNA degradation by a ferric bleomycin complex and slightly inhibited
peroxidation of arachidonic acid by the myoglobin-H2O2 system. Under certain circumstances, DHLA accelerated the loss of activity of alpha-antiproteinase exposed to ionizing radiation under a N2O/O2 atmosphere and also the loss of creatine kinase activity in human plasma exposed to gas-phase cigarette smoke. Neither LA nor DHLA reacted with superoxide radical (O.2-) or H2O2 at significant rates, but both were good scavengers of trichloromethylperoxyl radical (CCl3O2.). We conclude that LA and DHLA have powerful antioxidant properties. However, DHLA can also exert pro-oxidant properties, both by its iron ion-reducing ability and probably by its ability to generate reactive sulphur- containing radicals that can damage certain proteins, such as alpha 1-antiproteinase and creatine kinase. |
| A-2369 Suzuki YJ; Tsuchiya M; Packer L:Antioxidant activities of dihydrolipoic acid and its structural homologues.: Free Radic Res Commun: 18:2:115-22 (1993) |
| The relationships between
structure and antioxidant activity of dihydrolipoic acid (DHLA) were studied using
homologues of DHLA: bisonor-DHLA (a derivative which lacks two carbons in the hydrophobic
tail), tetranor-DHLA (which lacks four carbons) and a methyl ester derivative. It was observed that: i) DHLA homologues with shorter hydrocarbon tails (i.e., bisnor- and tetranor-DHLA) had greater ability to quench superoxide radicals (O2-); ii) no differences among homologues with different chain lengths were found for peroxyl radical (ROO.) scavenging in aqueous solution, and iii) DHLA was the best membrane antioxidant in terms of ROO. scavenging and lipid peroxidation inhibition. Differences among the DHLA homologues in their antioxidant properties in polar and apolar environments generally agreed with differences in their partition coefficients. The methyl ester was the least effective antioxidant both in aqueous phase and in membranes.Tetranor-DHLA was found not only to be less effective in preventing ROO.-induced lipid peroxidation, but also to induce lipid peroxidation in the presence of residual iron. Thus, the complexity of biological systems seems to complicate generalizations on the correlation of molecular structure with antioxidant activity of DHLA. |
| A-3241 Suzuki YJ; Aggarwal BB; Packer L: Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells.: Biochem Biophys Res Commun: 189:3:1709-15 (1992) |
| Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation.The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha- lipoic acid, prior to the stimulation of cells was found to inhibit NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 13- acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be effective in AIDS therapeutics. |
| A-3966 Whiteman M; Tritschler H; Halliwell B: Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase inactivation by oxidized and reduced lipoic acid.FEBS Lett: 379:1:74-6 (1996) |
| Peroxynitrite, formed by
combination of superoxide radical with nitric oxide, is a reactive tissue-damaging species
apparently involved in the pathology of several human diseases. Peroxynitrite nitrates
tyrosine residues and inactivates alpha 1-antiproteinase. We show that both lipoic acid
and dihydrolipoic acid efficiently protect against damage by peroxynitrite. By contrast,
other disulphides tested did not. The biological antioxidant effects of
lipoate/dihydrolipoate may involve scavenging of reactive nitrogen species as well as
reactive oxygen species.
|
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