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Lipoic acid
File:R-(+)-Lipoic-acid-2D-skeletal.png
File:R-(+)-Lipoic-acid-3D-vdW.png
Identifiers
CAS number 1200-22-2 Yes check.svgY
PubChem 6112
MeSH Lipoic+acid
SMILES
Properties
Molecular formula C8H14O2S2
Molar mass 206.33 g/mol
Appearance yellow needle-like crystals
Solubility in water sodium salt is readily soluble in water
Pharmacology
Bioavailability 30% (oral)[1]
 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Lipoic acid (LA) is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms (at C6 and C8) attached via a disulfide bond and is thus considered to be oxidized (although either sulfur atom can exist in higher oxidation states). The carbon atom at C6 is chiral and the molecule exists as two enantiomers R-(+)-lipoic acid (RLA) and S-(-)-lipoic acid (SLA) and as a racemic mixture R/S-lipoic acid (R/S-LA). Only the R-(+)-enantiomer exists in nature and is an essential cofactor of four mitochondrial enzyme complexes[2]. LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring. Endogenously synthesized RLA is essential for life and aerobic metabolism. Both RLA and R/S-LA are available as over-the-counter nutritional supplements and have been used nutritionally and clinically since the 1950’s. The relationship between endogenously synthesized (enzyme–bound) RLA and administered “free” RLA or R/S-LA has not been fully characterized but “free” plasma and cellular levels increase rapidly after oral consumption or intravenous injections."Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Although the intracellular milieu is strongly reducing, both free LA and its reduced form, dihydrolipoic acid (DHLA) have been detected within cells after administration of LA. Most endogenously produced RLA is not “free”, because octanoic acid, the precursor to RLA is attached to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached via an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor in aerobic metabolism, specifically the pyruvate dehydrogenase complex (PDC or PDHC). Endogenous (enzyme-bound) R- lipoate also participates in transfer of acyl groups in the α-keto-glutarate dehydrogenasecomplex (KDHC or OGDC) and the branched-chain oxo acid dehydrogenase complex (BCOADC). RLA transfers a methylamine group in the glycine cleavage complexes (GCV). RLA serves as co-factor to the acetoin dehydrogenous complex (ADC) catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source.

Contents

Introduction

RLA is essential for life and aerobic metabolism. SLA is unnatural and a chemical byproduct of achiral manufacturing processes [3]. SLA is generally considered safe and non-toxic, except in the case of thiamine deficiency where its presence as the single enantiomer or as a 50% component of the racemic mixture proved fatal to rats [4][5]. RLA is essential to metabolism and to all forms of life ever since mitochondria merged with primitive cells at least a billion years ago [6]. SLA and R/S-LA did not exist prior to chemical synthesis in 1952 [7][8]. Due to the low cost and ease of manufacturing R/S-LA relative to RLA, the racemic form was more widely used clinically in Europe and Japan in the 1950’s to 1960’s despite the early recognition that the various forms of LA were not bioequivalent [9]. The first synthetic procedures appeared for RLA and SLA in the mid 1950’s [10][11][12][13].

R/S-LA was approved for treatment of diabetes in Germany in 1966 [14]. Japanese and German manufactured R/S-LA became available as a nutritional supplement in the US in the late 1980’s but interest and use grew exponentially after Professor Lester Packer presented it as a "miracle antioxidant" on an episode of ABC Nightline in 1999. Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. Currently most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa [15][16]. Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechansims of action but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form) [17][18].

All of the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes; glutathione reductase (GR) and thioredoxin reductase (Trx1) and two mitochondrial enzymes lipoamide dehydrogenase and thioredoxin reductase (Trx2) reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. R-(+)-lipoic acid is enzymatically or chemically reduced to R-(-)-dihydrolipoic acid whereas S-(-)-lipoic acid is reduced to S-(+)-dihydrolipoic acid [19][20][21][22][23][24][25]. Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions [26].

The cytosolic and mitochondrial redox state is maintained in a reduced state relative to the extracellular matrix and plasma due to high concentrations of glutathione [27][28]. Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms [29]. Free LA is rapidly metabolized to a variety of shorter chain metabolites (via β-oxidation and either mono or bis-methylation) that have been identified and quantified intracellularly, in plasma and in urine [30][31].

While it has been stated that “free-RLA” (non-enzyme bound) has not been detected in humans, baseline levels (prior to supplementation) of RLA and R-DHLA have been detected at low levels in human plasma [32]. RLA has been detected at 12.3-43.1 ng/mL following acid hydrolysis. Enzymatic hydrolysis released 1.4-11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively [33][34][35]. It has not been determined whether pre-supplementation levels of RLA derive from food sources, mitochondrial turnover and salvaging or from gut microbes but low levels have been correlated to a variety of disease states [36][37][38][39].

Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the R-lipoic acid-L-lysine amide bond [40]. Both synthetic lipoamide and R-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases which release free R-lipoic acid and either L-lysine or ammonia into the bloodstream [41][42][43][44][45][46]. It has recently been questioned whether or not food sources of RLA provide any measurable benefit nutritionally or therapeutically due to the very low concentrations present [47]. Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiological conditions. Most endogenous RLA is not “free”, because octanaote is attached to the enzyme complexes that use it via LipA. The sulfur atoms derive from the amino acid L-cysteine and add asymmetrically to octanoate by lipoate synthase, thus generating the chiral center at C6 [48]. Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles [49][50]. It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2) [51].

As a co-factor, RLA is covalently bonded via an amide linkage to a terminal lysine residue of the various lipoyl domains. The most well studied role of endogenous RLA is as a co-factor in aerobic metabolism, specifically the pyruvate dehydrogenase complex (PDH) which contains three subunits, E1, E2 and E3. At E1 pyruvate is oxidized to acetate and carbon dioxide. At E2, in the reduced form (bound R-DHLA) the acetyl group is transferred to coenzyme A yielding acetyl coenzyme A. At E3, R-DHLA is re-oxidized to RLA with the generation of NADH [52]. Lipoate also participates in transfer of acyl groups in two other mitochondrial 2-oxoacid dehydrogenases (α-ketoglutarate dehydrogenase complex [KGDH] and the branched chain oxo-acid dehydrogenase complex [BCDH]. In addition to acyl transfer reactions RLA also transfers a methylamine group in the glycine cleavage complexes [53][54][55][56].

History

RLA prior to isolation and characterization was also known as protogen A, acetate-replacing factor and pyruvate oxidation factor (POF) [57][58]. This followed from the observation that essential growth factors (later shown to be RLA) were required for enterococci and other microorganisms to oxidatively decarboxylate pyruvate to acetate. These organisms lack the ability to synthesize R-lipoate and thus need to obtain it from the environment [59][60][61][62]. Dextro-(+)-LA (~30 mg) was isolated in a crystalline form by Lester Reed in 1951 from ~10 tons of beef liver [63][64]. Characterization of the yellow crystals was made in a collaborative effort between Gunsalus, Reed and chemists at Eli Lilly who proved the natural isolate contained an aliphatic chain of eight carbons, two sulfur atoms (one of which was terminal), was acidic, and by polarimetry the dextro-(+)-configuration [65]. Prior to complete structural identity and characterization it was proposed that isomers of the naturally occurring form could be designated according to which carbon atom in the octanoic acid chain the secondary sulfur atom was attached. Originally, 4, 5 or 6-thioctic acid were possible candidates for the correct structure for RLA, depending on attachment of sulfur at C4, C5 or C6, respectively. Synthesis of the racemic compound (R/S)-LA in 1952 proved the tentative assignment of 6-thioctic acid had been correct [66][67][68]. The trivial name “α-lipoic acid” was proposed by Reed (and subsequently accepted) due to its lipophilicity (fat loving) quality and by fact of it being a carboxylic acid [69]. Reed designated the newly isolated compound “alpha” in order to differentiate it from a second isolated oxidized compound which was designated “β-lipoic acid” [70]. The configuration of the natural form was proposed in 1955 by comparison of the melting point-composition diagrams of R-(+)-3-methyloctanedioic acid with (+) and (-)- 3-mercaptooctanedioic acids but it was not proven to contain the R-absolute configuration (using the Cahn-Ingold-Prelog priority rules) until 1983 when the unnatural antipode was enantioselectively synthesized from S-malic acid [71][72][73].

The first animal pharmacokinetic profiles of R/S-LA were presented by Prof Leonardo Donatelli at the International Symposium on Thioctic Acid in Naples (1955) who also presented an impressive and potent list of anti-toxin effects of LA against a wide variety of chemical toxins. This lecture stimulated world interest in discovering new applications for LA apart from its uses as a “vitamin-like” substance [74]. Subsequent studies in Europe and Japan expanded the number of clinical applications as well as the number of chemical toxins that LA protected against, including radiation [75][76][77][78][79][80][81][82][83][84][85][86][87][88][89]. The radio-protective effects of LA encouraged a significant research effort in Japan, the United States, Germany, Italy and the Soviet Union after World War II as a potential antidote for nuclear fall out and radiation poisoning and later proved beneficial in treating the victims of the Chernobyl disaster [90][91]. Multiple reports in Europe of use of LA for treatment of amanita mushroom poisoning appeared [92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111]. The pharmaceutical industry flourished in Japan after World War II and thioctic acid (LA) was developed as a public health compound by several Japanese firms, including Takeda, Yamanouchi, Fujisawa, Daiichi Seikaku and Rohto who also manufactured B-vitamins and a number of compounds covalently linking thiamine and LA. In the 1950’s and early 1960’s LA was actively researched and/or under commercial development by The Research Foundation of New York, Eli Lilly Corporation, Merck, Sharpe & Dohme, Dupont and American Cyanamid-Lederle Laboratories in the United States and numerous patents for new manufacturing methods and uses were granted. There was great interest for using LA in disorders involving “energy-impairment” (ref needed). The first human clinical studies using LA in the United States were conducted by Fredrick C. Bartter, Burton M. Berkson, and associates from the National Institutes of Health (NIH) in the 1970’s [112][113][114].


Drs. Bartter and Berkson administered LA intravenously to 79 people with acute and severe liver damage at various medical centers across the United States and 75 recovered full liver function. They were appointed by the FDA as principal investigators for this therapeutic agent as an investigational drug. Dr. Berkson went on to use it successfully for the treatment of chronic liver diseases (viral hepatitis, autoimmune hepatitis, etc) [115]. The original rationale for using R/S-lipoic acid (LA) as a nutritional supplement and therapeutically was that RLA was known to behave biochemically like a B-vitamin (acting as a substrate or co-factor essential for enzyme function) and due to the fact that lower endogenous concentrations of RLA were found in tissues of humans with various diseases. It was believed that supplementation would restore normal levels leading to restoration of healthy function and that SLA was essentially inert [116][117][118][119][120]. SLA was believed to be essentially non-bioactive and existed in vivo as isomeric ballast up to the mid-1950s since microbial assays used to quantify LA, were almost completely stereospecific for RLA[121][122]. This was shown to be false in an animal model when selective toxicity for both R/S-LA and SLA was demonstrated in thiamine deficient rats. RLA, alone was non-toxic. This study demonstrated the first case of competitive inhibition of SLA toward the RLA found as a 50% component of the racemic mixture and may have relevance to human thiamine deficiency [123][124]. In a second case of a stereospecific antitoxin effect only RLA but not SLA was able to reverse the selective toxicity of an arsenical poison in heart mitochondria [125][126]. The stereospecific anti-toxin effect of RLA is now believed to occur by activation of the stress responsive Nrf2 transcription factor which activates a battery of cytoprotective genes via the antioxidant response element, induces Phase II detoxification enzymes thus indirectly improving the antioxidant status of the cell [127]. RLA, in vivo is more accurately labeled a stereospecific redox modulator (since Nrf2 is redox controlled) or a stereospecific cytoprotective agent rather than an antioxidant ( i.e. direct scavenger of free radicals). This contention is supported by the fact that even high doses of RLA lead to low micro Molar concentrations intracellularly whereas glutathione and ascorbic acid, the primary redox buffers are present at milli Molar concentrations.

Biosynthesis and attachment

The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis or β-oxidation of long chain fatty acids. In eukaryotes a second fatty acid biosynthetic pathway in the mitochondria is used for this purpose[128][129]. The octanoate is transferred from a thioester of acyl carrier protein to an amide of the lipoyl domain by an octanoyltransferase. The sulfur centers are inserted into the 6th and 8th carbons of octanoate via the a radical s-adenosyl methionine mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide.[130] As a result, lipoic acid is synthesized on the lipoyl domain and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by the action of a specific enzyme, called lipoamidase[131]. Free lipoic can be attached to the lipoyl domain by the enzyme lipoate protein ligase. Like all ligases, this enzyme requires ATP. Lipoate protein ligases proceed via an enzyme bound lipoyl adenylate intermediate.[132]

Lipoic acid-dependent complexes

2-OADH transfer reactions occur by a similar mechanism in the PDH complex, 2-oxoglutarate dehydrogenase (OGDH) complex, branched chain oxoacid dehydrogenase (BCDH) complex, and acetoin dehydrogenase (ADH) complex. The most studied of these is the PDH complex. These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.[133][134] The geometry of the PDH E2 core is cubic in Gram-negative bacteria or dodecahedral in Eukaryotes and Gram-positive bacteria. Interestingly the 2-OGDH and BCDH geometry is always cubic.[135] The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.[136] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[137]

The glycine cleavage system differs from the other complexes, and has a different nomenclature. In this complex the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase (SHMT) to synthesize serine from glycine. This system is used by many organisms and plays a crucial role in the photosynthetic carbon cycle.[138]

Biological sources

Lipoic acid is found in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[139][140] Naturally occurring lipoic acid is always covalently bound and not immediately available from dietary sources. Additionally, the amount of lipoic acid present is very low. For example: the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.[141] As a result, all lipoic acid available as a supplement is chemically synthesized.

Use as a dietary supplement

Since the mid-1950’s the overlapping nutritional and clinical uses of LA have been recognized and commercially developed. RLA is a classic example of an orthomolecular nutrient, in the original sense of Linus Pauling. Due to the low cost and ease of manufacturing R/S-LA relative to RLA, as well as early successes in treatments, the racemic form was more widely used nutritionally and clinically in Europe and Japan despite the early recognition that the various forms of LA were not bioequivalent [142]. The original rationale for using R/S-lipoic acid (LA) as a nutritional supplement was that endogenous RLA was known to have biochemical properties like a B-vitamin (acting as a substrate or co-factor essential for enzyme function). It was also recognized that lower endogenous concentrations of RLA were found in tissues of humans with various diseases and lower levels of RLA were found in the 24 hour urine of patients with various diseases than in healthy subjects[143][144][145][146][147] . Injections of R/S-LA as low as 10–25 mg normalized daily urinary output and in many cases improved patient health (ref needed). When it was demonstrated that mammals have the genes to endogenously synthesize RLA, it lost vitamin status but is today considered to be a “conditionally essential nutrient.” [148]. The exact mechanisms of how RLA levels decline with age and in various progressive diseases is unknown. In addition, microbial assays used to quantify LA were essentially stereospecific for RLA (100% active for RLA, 0% activity for SLA) so it was believed that SLA was essentially inert or of very low biological activity. This was proven false by Gal who demonstrated stereospecific toxicity of the S-enantiomer in thiamine- deficient rats[149][150].

LA was recognized to have antioxidant potential in 1959 and was used as a preservative for lard and cooking oils but it would take another 40 years for this property to gain significant public attention and application in maintaining or restoring human health[151]. In the early 1960’s R/S-LA was marketed internationally both as a drug and a nutrient by Fujisawa Pharmaceuticals and Takeda Pharmaceuticals under the tradenames Tioctan and Biletan. In Italy, Farmachimica Cutolo-Calosi (Naples) was one of the first companies to commercially develop R/S-LA as well as R/S-thioctamide and R/S-dihydrothioctamide.

In the mid-1960's, Chemiewerk Homborg in Frankfurt, Germany (re-named Asta Medica in 1985 and the pharma division of Degussa) began supplying the European market with R/S-LA under the trade name Thioctacid. In the late 1980’s, Heinz Ulrich, M.D. of Chemiewerk Homborg began a reinvestigation of the differences between RLA, SLA and R/S-LA, experimentally and clinically. Ulrich began the new era in modern RLA research [152]. Ulrich contacted Professor Lester Packer from UC Berkeley in order to encourage further research efforts into elucidating the mechanisms of action of LA and to help expand nutritional and clinical applications of LA internationally.

Japanese and German manufactured R/S-LA became available as a nutritional supplement in the US in the late 80’s and sales and use grew slowly and steadily throughout the 90’s as interest in antioxidants and free radicals grew due to recognition of the roles of reactive oxygen and reactive nitrogen species in health, disease and the aging process.

Interest and use of LA grew exponentially after Dr Packer presented it on an episode of ABC Nightline in 1999 where it was hailed as a “miracle antioxidant” (ref needed). LA, carnitine or acetyl carnitine were recommended as "bioenergy supplements" and the demand grew for RLA along with R/S-LA after several papers by Professor Bruce Ame’s research group (also from UC Berkeley) found RLA and acetyl carnitine reversed age-related markers in old rats to youthful levels[153][154] [155][156][157][158][159].

Today R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets and aqueous liquids and have been branded as “antioxidants.” This label has recently been challenged [160]. In Japan LA is marketed primarily as a "weight loss" and "energy" supplement.

No Recommended Daily Allowance (RDA) has been established and the relationships between supplemental doses and therapeutic doses have not been clearly defined.

Daily oral doses of either RLA or R/S-LA range from < 10 mg/ dosage form in multi-vitamin formulations up to 600 mg as a stand alone product. Higher doses up 1800 mg have been used therapeutically and doses as high as 4-5 g/day have been recommended for treatment of HIV and cancer (ref needed). RLA may function in vivo like a B-vitamin and at higher doses like plant derived nutrients such as curcumin, sulphoraphane, resveratrol, other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents [161][162].

Due to its high stability and bioavailability R-lipoic acid sodium salt (NaRLA) relative to the free acid form of RLA, NaRLA is being used in a federally funded clinical trial for multiple sclerosis at Oregon Health and Science University. [163].

R-lipoic acid (RLA) is currently being used in the form of sodium R-lipoate (NaRLA) in two federally funded clinical trials at Oregon State University to test its effects in preventing heart disease and atherosclerosis [164] [165].

Antioxidant & Prooxidant Effects of Lipoic Acid & Dihydrolipoic acid

The antioxidant effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C and vitamin E deficiency[166]. LA is reduced intracellularly to dihydrolipoic acid which in cell culture regenerates by reduction antioxidant radicals, such as vitamin C and vitamin E[167]. LA is able to scavenge reactive oxygen and reactive nitrogen species in vitro due to long incubation times but there is little evidence this occurs in vivo or that radical scavenging contributes to the primary mechanisms of action of LA [168][169].The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects[170]. This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins[171]. Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription which improves the antioxidant status of the cell. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects[172][173][174].

Disease Treatment

Lipoic acid has been shown in cell culture experiments to increase cellular uptake of glucose by recruiting the glucose transporter GLUT4 to the cell membrane, suggesting its use in diabetes,[175][176] although these findings are controversial as lipoic acid worsened the condition of type 1 diabetes induced rats.[177] Studies of rat aging have suggested that the use of Acetyl-L-carnitine and lipoic acid results in improved memory performance and delayed structural mitochondrial decay.[178] As a result, it may be helpful for people with Alzheimer's disease or Parkinson's disease.[179] In 2009 a study found that it reduced triglycerides in mice.[180]

ALA has been used for the treatment of various cancers for which no effective treatments exist.[181][182]

Use as a chelator

Owing to the presence of two thiol groups, dihydrolipoic acid is a chelating agent. Lipoic acid administration can significantly enhance biliary excretion of inorganic mercury in rat experiments, although it is not known if this is due to chelation by lipoic acid or some other mechanism.[183] Lipoic acid has the potential to cross the blood-brain barrier in humans unlike DMSA and DMPS, however its effectiveness is heavily dependent on the dosage and frequency of application.[184]

Evidence that R-Lipoic Acid, S-Lipoic Acid and R/S-Lipoic Acid are Pharmacologically Distinct

Only the R-enantiomer (RLA) of LA occurs naturally. Theoretically the S-enantiomer (SLA) can assist in the reduction of the RLA when a racemic (50% R-enantiomer and 50% S-enantiomer) mixture is given but this is of questionable relevance in vivo [185][186]. Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[187][188][189][190][191][192][193] [194][195][196][197][198][199][200]. Furthermore, while a racemic mixture of LA has been found to increase the expression of GLUT4, responsible for glucose uptake in cells, RLA has been shown to do so by a greater amount than either the SLA or R/S-LA [201]. This indicates that the specific effects of RLA may be inhibited when SLA is present. According to the Linus Pauling Institute website (written by the late Jane Higdon, Ph.D and reviewed by Tory Hagen Ph.D.) virtually all of the published studies of LA supplementation in humans up through 2006 used R/S- LA [202]. Since that time several studies from Hagen’s group have shown that contrary to popular belief LA is not primarily an in vivo free radical scavenger but rather an inducer of a beneficial stress response that indirectly improves the antioxidant capacity of the cell.[203][204]. This ability is 100% stereospecific for RLA and is mediated by the stress responsive transcription factor, Nrf2 [205]. A recent human pharmacokinetic study of RLA demonstrated that the maximum concentration in plasma (Cmax) and the area under the curve ( AUC, a measure of bioavailability) are significantly greater than any other oral dosage forms when administered in the form of a salt and rivals plasma levels achieved by intravenous administration [206]. Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved. RLA sodium (NaRLA) due to its high bioavailability has been suggested to be the superior form of LA for nutraceutical and pharmaceutical applications [207][208][209].

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Other reviews


Lipoic acid
Identifiers
CAS number 1200-22-2 Y
PubChem 6112
MeSH Lipoic+acid
SMILES
Properties
Molecular formula C8H14O2S2
Molar mass 206.33 g/mol
Appearance yellow needle-like crystals
Solubility in water sodium salt is readily soluble in water
Pharmacology
Bioavailability 30% (oral)[1]
Related compounds
Related compounds Lipoamide
Asparagusic acid
 Y (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Lipoic acid (LA) is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms (at C6 and C8) attached via a disulfide bond and is thus considered to be oxidized (although either sulfur atom can exist in higher oxidation states). The carbon atom at C6 is chiral and the molecule exists as two enantiomers R-(+)-lipoic acid (RLA) and S-(-)-lipoic acid (SLA) and as a racemic mixture R/S-lipoic acid (R/S-LA). Only the R-(+)-enantiomer exists in nature and is an essential cofactor of four mitochondrial enzyme complexes.[2] Endogenously synthesized RLA is essential for life and aerobic metabolism. Both RLA and R/S-LA are available as over-the-counter nutritional supplements and have been used nutritionally and clinically since the 1950s for a number of diseases and conditions.

The relationship between endogenously synthesized (enzyme–bound) RLA and administered “free” RLA or R/S-LA has not been fully characterized but “free” plasma and cellular levels increase rapidly after oral consumption or intravenous injections. "Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Although the intracellular environment is strongly reducing, both free LA and its reduced form, dihydrolipoic acid (DHLA) have been detected within cells after administration of LA. Most endogenously produced RLA is not “free”, because octanoic acid, the precursor to RLA, is attached to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached via an amide bond to a terminal lysine residue of the enzyme’s lipoyl domains. One of the most studied roles of RLA is as a cofactor in aerobic metabolism, specifically the pyruvate dehydrogenase complex (PDC or PDHC). Endogenous (enzyme-bound) R- lipoate also participates in transfer of acyl groups in the α-keto-glutarate dehydrogenase complex (KDHC or OGDC) and the branched-chain oxo acid dehydrogenase complex (BCOADC). RLA transfers a methylamine group in the glycine cleavage complex (GCV). RLA serves as co-factor to the acetoin dehydrogenase complex (ADC) catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source. LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.

Contents

Introduction

RLA is essential for life and aerobic metabolism. SLA is unnatural and a chemical byproduct of achiral manufacturing processes.[3] SLA is generally considered safe and non-toxic, except in the case of thiamine deficiency where its presence as the single enantiomer or as a 50% component of the racemic mixture proved fatal to rats.[4][5] RLA is essential to metabolism and to all forms of life ever since mitochondria merged with primitive cells at least a billion years ago.[6] SLA and R/S-LA did not exist prior to chemical synthesis in 1952.[7][8] Due to the low cost and ease of manufacturing R/S-LA relative to RLA, the racemic form was more widely used clinically in Europe and Japan in the 1950’s to 1960’s despite the early recognition that the various forms of LA were not bioequivalent.[9] The first synthetic procedures appeared for RLA and SLA in the mid 1950s.[10][11][12][13]

R/S-LA was approved for treatment of diabetes in Germany in 1966.[14] Japanese and German manufactured R/S-LA became available as a nutritional supplement in the US in the late 1980s but interest and use grew exponentially after Professor Lester Packer presented it as a "miracle antioxidant" on an episode of ABC Nightline in 1999. Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. Currently most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.[15][16] Although RLA is favored nutritionally due to its “vitamin-like” role in metabolism both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechansims of action but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).[17][18]

All of the disulfide forms of LA (R/S-LA, RLA and SLA) can be reduced to DHLA although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes; glutathione reductase (GR) and thioredoxin reductase (Trx1) and two mitochondrial enzymes lipoamide dehydrogenase and thioredoxin reductase (Trx2) reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. R-(+)-lipoic acid is enzymatically or chemically reduced to R-(-)-dihydrolipoic acid whereas S-(-)-lipoic acid is reduced to S-(+)-dihydrolipoic acid.[19][20][21][22][23][24][25] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions [26].

The cytosolic and mitochondrial redox state is maintained in a reduced state relative to the extracellular matrix and plasma due to high concentrations of glutathione.[27][28] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[29] Free LA is rapidly metabolized to a variety of shorter chain metabolites (via β-oxidation and either mono or bis-methylation) that have been identified and quantified intracellularly, in plasma and in urine.[30][31]

While it has been stated that “free-RLA” (non-enzyme bound) has not been detected in humans, baseline levels (prior to supplementation) of RLA and R-DHLA have been detected at low levels in human plasma [32]. RLA has been detected at 12.3-43.1 ng/mL following acid hydrolysis. Enzymatic hydrolysis released 1.4-11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively [33][34][35]. It has not been determined whether pre-supplementation levels of RLA derive from food sources, mitochondrial turnover and salvaging or from gut microbes but low levels have been correlated to a variety of disease states [36][37][38][39].

Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the R-lipoic acid-L-lysine amide bond [40]. Both synthetic lipoamide and R-lipoyl-L-lysine are rapidly cleaved by serum lipoamidases which release free R-lipoic acid and either L-lysine or ammonia into the bloodstream [41][42][43][44][45][46]. It has recently been questioned whether or not food sources of RLA provide any measurable benefit nutritionally or therapeutically due to the very low concentrations present [47]. Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiological conditions. Most endogenous RLA is not “free”, because octanaote is attached to the enzyme complexes that use it via LipA. The sulfur atoms derive from the amino acid L-cysteine and add asymmetrically to octanoate by lipoate synthase, thus generating the chiral center at C6 [48]. Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles [49][50]. It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2) [51].

As a co-factor, RLA is covalently bonded via an amide linkage to a terminal lysine residue of the various lipoyl domains. The most well studied role of endogenous RLA is as a co-factor in aerobic metabolism, specifically the pyruvate dehydrogenase complex (PDH) which contains three subunits, E1, E2 and E3. At E1 pyruvate is oxidized to acetate and carbon dioxide. At E2, in the reduced form (bound R-DHLA) the acetyl group is transferred to coenzyme A yielding acetyl coenzyme A. At E3, R-DHLA is re-oxidized to RLA with the generation of NADH [52]. Lipoate also participates in transfer of acyl groups in two other mitochondrial 2-oxoacid dehydrogenases (α-ketoglutarate dehydrogenase complex [KGDH] and the branched chain oxo-acid dehydrogenase complex [BCDH]. In addition to acyl transfer reactions RLA also transfers a methylamine group in the glycine cleavage complexes [53][54][55][56].

Biosynthesis and attachment

The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl acyl carrier protein. In eukaryotes a second fatty acid biosynthetic pathway in the mitochondria is used for this purpose.[57][58] The octanoate is transferred from a thioester of acyl carrier protein to an amide of the lipoyl domain by an octanoyltransferase. The sulfur centers are inserted into the 6th and 8th carbons of octanoate via the a radical s-adenosyl methionine mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide.[59] As a result, lipoic acid is synthesized on the lipoyl domain and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by the action of a specific enzyme, called lipoamidase.[60] Free lipoate can be attached to the lipoyl domain by the enzyme lipoate protein ligase. The ligase activity of this enzyme requires ATP. Lipoate protein ligases proceed via an enzyme bound lipoyl adenylate intermediate.[61]

Lipoic acid-dependent complexes

2-OADH transfer reactions occur by a similar mechanism in the PDH complex, 2-oxoglutarate dehydrogenase (OGDH) complex, branched chain oxoacid dehydrogenase (BCDH) complex, and acetoin dehydrogenase (ADH) complex. The most studied of these is the PDH complex. These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites.[62][63] The geometry of the PDH E2 core is cubic in Gram-negative bacteria or dodecahedral in Eukaryotes and Gram-positive bacteria. Interestingly the 2-OGDH and BCDH geometry is always cubic.[64] The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.[65] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[66]

The glycine cleavage system differs from the other complexes, and has a different nomenclature. In this complex the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate (THF) yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase (SHMT) to synthesize serine from glycine. This system is used by many organisms and plays a crucial role in the photosynthetic carbon cycle.[67]

Biological sources

Lipoic acid is found in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[68][69] Naturally occurring lipoic acid is always covalently bound and not immediately available from dietary sources. Additionally, the amount of lipoic acid present is very low. For example: the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.[70] As a result, all lipoic acid available as a supplement is chemically synthesized.

Use of lipoic acid as a dietary supplement

The possibility of an RLA deficiency state was first proposed by Franz Rausch M.D. at the International Symposium on Thioctic Acid (1955) who presented clinical data indicating patients suffering from various diseases benefitted by “high doses” (25-50 mg/day) of intravenous LA which were well tolerated and free of side effects. Rausch claimed patients in hepatic coma were revived by intravenous LA. Dr A Colarusso confirmed the findings of Rausch. Italian researcher, Umberto Butturini (University of Bologna) provided preliminary clinical and experimental observations on LA in humans. Butturini reported a moderate anti-steatogenic effect of thioctic acid which also gave fair protection against carbon tetrachloride toxicity. LA restored liver glycogen and the sulfhydryl content in physiological and experimental hepato-pathologic conditions but was ineffective in treating portal cirrhosis or alloxan-induced diabetes. Later Cutolo and Reduzzi (Laboratorio Ricerche dell'Istituto Sieroterapico Italiano, Naples) claimed to successfully treat alloxan-induced diabetes[71]. Dr P. Introzzi (University of Pavia) presented case histories of four cases of hepatic cirrhosis, two of congestive heart failure and two of chronic hepatitis. One case of hepatic cirrhosis and both cases of chronic hepatitis responded favorably.

LA was shown to be hepatoprotective [72][73][74][75], improve liver circulation [76], treat chronic liver diseases [77][78][79][80][81][82][83], various liver diseases such as [84]jaundice,[85]hepatitis,[86][87]cirrhosis,[88][89]hepatic coma,[90][91][92][93][94][95], diabetes [96][97][98], alter carbohydrate metabolism[99][100], diabetic neuropathy [101][102]alter histidine metabolic disorders,[103], alter blood pyruvate and lactate levels [104][105][106], psychiatric diseases [107]Botkin’s disease,[108], antimony poisoning [109], mercury poisoning [110], atherosclerosis [111], coronary atherosclerosis [112], cerebrovascular diseases [113], ethionine-damaged liver [114][115], potassium cyanide poisoning [116], streptomycin intoxication [117], mushroom poisoning [118][119], lower cholesterol [120], reverse barbiturate anesthesia [121], experimentally reduce voluntary alcohol intake [122][123], and augment potassium tolerance [124].

One of the most studied clinical uses of LA is the treatment of diabetes and diabetic neuropathy[125]

LA has also been used experimentally and/or clinically to prevent organ dysfunction [126], reduce endothelial dysfunction and improve albuminuria [127][128], treat or prevent cardiovascular disease [129], accelerate chronic wound healing [130], reduce levels of ADMA in diabetic end-stage renal disease patients on hemodialysis [131], burning mouth syndrome [132][133][134], reduce iron overload [135], treat metabolic syndrome [136][137][138], improve or prevent age-related cognitive dysfunction [139][140], prevent or slow the progression of Alzheimer’s Disease [141][142][143], prevent erectile dysfunction (animal models but anecdotally applies to humans as well) [144][145], prevent migraines [146], treat multiple sclerosis [147][148][149], treat chronic diseases associated with oxidative stress [150]reduce inflammation,[151], inhibit advanced glycation end products (AGE),[152], treat peripheral artery disease [153].

Since the mid-1950s the overlapping nutritional and clinical uses of LA have been recognized and commercially developed. RLA is a classic example of an orthomolecular nutrient, in the original sense of Linus Pauling. Due to the low cost and ease of manufacturing R/S-LA relative to RLA, as well as early successes in treatments, the racemic form was more widely used nutritionally and clinically in Europe and Japan despite the early recognition that the various forms of LA were not bioequivalent [154]. The original rationale for using R/S-lipoic acid (LA) as a nutritional supplement was that endogenous RLA was known to have biochemical properties like a B-vitamin (acting as a substrate or co-factor essential for enzyme function). It was also recognized that lower endogenous concentrations of RLA were found in tissues of humans with various diseases and lower levels of RLA were found in the 24 hour urine of patients with various diseases than in healthy subjects[155][156][157][158][159] . Injections of R/S-LA as low as 10–25 mg normalized daily urinary output and in many cases improved patient health (ref needed). When it was demonstrated that mammals have the genes to endogenously synthesize RLA, it lost vitamin status but is today considered to be a “conditionally essential nutrient.” [160]. The exact mechanisms of how RLA levels decline with age and in various progressive diseases is unknown. In addition, microbial assays used to quantify LA were essentially stereospecific for RLA (100% active for RLA, 0% activity for SLA) so it was believed that SLA was essentially inert or of very low biological activity. This was proven false by Gal who demonstrated stereospecific toxicity of the S-enantiomer in thiamine- deficient rats[161][162].

LA was recognized to have antioxidant potential in 1959 and was used as a preservative for lard and cooking oils but it would take another 40 years for this property to gain significant public attention and application in maintaining or restoring human health[163]. In the early 1960s R/S-LA was marketed internationally both as a drug and a nutrient by Fujisawa Pharmaceuticals and Takeda Pharmaceuticals under the tradenames Tioctan and Biletan. In Italy, Carlo Erba SpA (Milan) and Farmachimica Cutolo-Calosi (Naples) were two of the first companies to commercially develop R/S-LA as well as R/S-thioctamide and R/S-dihydrothioctamide.

In the mid-1960s, Chemiewerk Homburg in Frankfurt, Germany (re-named Asta Medica in 1985 and the pharma division of Degussa) began supplying the European market with R/S-LA under the trade name Thioctacid from raw material provided by Carlo Erba SpA. In the late 1980s, Heinz Ulrich, M.D. of Chemiewerk Homburg began a reinvestigation of the differences between RLA, SLA and R/S-LA, experimentally and clinically. Ulrich began the new era in modern RLA research.[164] Ulrich contacted Professor Lester Packer from UC Berkeley in order to encourage further research efforts into elucidating the mechanisms of action of LA and to help expand nutritional and clinical applications of LA internationally.

Japanese and German manufactured R/S-LA became available as a nutritional supplement in the US in the late 80’s and sales and use grew slowly and steadily throughout the 1990s as interest in antioxidants and free radicals grew due to recognition of the roles of reactive oxygen and reactive nitrogen species in health, disease and the aging process.

Interest and use of LA grew exponentially after Dr Packer presented it on an episode of ABC Nightline in 1999 where it was hailed as a "miracle antioxidant".[citation needed] LA, carnitine or acetyl carnitine were recommended as "bioenergy supplements" and the demand grew for RLA along with R/S-LA after several papers by research group of Professor Bruce Ames (also from UC Berkeley) found RLA and acetyl carnitine reversed age-related markers in old rats to youthful levels[165][166] [167][168][169][170][171].

Today R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets and aqueous liquids and have been branded as antioxidants. This label has recently been challenged.[172] In Japan LA is marketed primarily as a "weight loss" and "energy" supplement.

No Recommended Daily Allowance (RDA) has been established and the relationships between supplemental doses and therapeutic doses have not been clearly defined.

Daily oral doses of either RLA or R/S-LA range from < 10 mg/ dosage form in multi-vitamin formulations up to 600 mg as a stand alone product. Higher doses up 1800 mg have been used therapeutically and doses as high as 4-5 g/day have been recommended for treatment of HIV and cancer (ref needed). RLA may function in vivo like a B-vitamin and at higher doses like plant derived nutrients such as curcumin, sulphoraphane, resveratrol, other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents [173][174].

Due to its high stability and bioavailability, relative to the free acid form of RLA, R-lipoic acid sodium salt (NaRLA) is being used in a federally funded clinical trial for multiple sclerosis at Oregon Health and Science University.[175]

R-lipoic acid (RLA) is currently being used in the form of sodium R-lipoate (NaRLA) in two federally funded clinical trials at Oregon State University to test its effects in preventing heart disease and atherosclerosis.[176][177]

Antioxidant and prooxidant effects of lipoic acid and dihydrolipoic acid

The antioxidant effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C and vitamin E deficiency[178]. LA is reduced intracellularly to dihydrolipoic acid which in cell culture regenerates by reduction antioxidant radicals, such as vitamin C and vitamin E[179]. LA is able to scavenge reactive oxygen and reactive nitrogen species in vitro due to long incubation times but there is little evidence this occurs in vivo or that radical scavenging contributes to the primary mechanisms of action of LA [180][181].The relatively good scavenging activity of LA toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects[182]. This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins[183]. Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription which improves the antioxidant status of the cell. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects[184][185][186].

Use as a chelator

Owing to the presence of two thiol groups, dihydrolipoic acid is a chelating agent. Lipoic acid administration can significantly enhance biliary excretion of inorganic mercury in rat experiments, although it is not known if this is due to chelation by lipoic acid or some other mechanism.[187] Lipoic acid has the potential to cross the blood-brain barrier in humans unlike DMSA and DMPS, however its effectiveness is heavily dependent on the dosage and frequency of application.[188]

Pharmacological differences of R-lipoic acid, S-lipoic acid, and R/S-lipoic acid

Only the R-enantiomer (RLA) of LA occurs naturally. The S-enantiomer (SLA) can assist in the reduction of the RLA when a racemic (50% R-enantiomer and 50% S-enantiomer) mixture is given.[189] Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[190][191][192][193][194][195][196][197]

Although RLA is more bioactive, racemic mixtures of lipoic acid can also be beneficial. A racemic mixture of LA has been found to increase the expression of GLUT4, responsible for glucose uptake in cells, RLA has been shown to do so by a greater amount than SLA.[198] Most studies of LA supplementation in humans up through 2006 used R/S- LA.[199]

More recently the primary effect of lipoic acid is not as an in vivo free radical scavenger, but rather an inducer of a beneficial stress response. This stress response indirectly improves the antioxidant capacity of the cell.[200] A recent human pharmacokinetic study of RLA demonstrated that the maximum concentration in plasma and bioavailability are significantly greater than any other oral dosage forms when administered in the form of a salt and rivals plasma levels achieved by intravenous administration.[201] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved. [202]

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