Also Known As: Lipoic acid, Alpha lipoid acid, α-lipoic acid, RLA, R lipoic acid, R-Lipoic acid, S Lipoic acid, S-Lipoic acid, SLA
Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) is anorganosulfur compound derived from octanoic acid. LA contains two sulfur atoms (at C6 and C8) connected by 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. Endogenously synthesized RLA is essential for 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 various diseases and conditions. LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.
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 and decrease rapidly after oral consumption or intravenous injections. "Lipoate" is theconjugate base of lipoic acid, and the most prevalent form of LA under physiologic conditions. Although the intracellular environment is strongly reducing, both free LA and its reduced form,dihydrolipoic acid (DHLA), have been detected in cells after administration of LA. Most endogenously produced RLA is not “free” because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by 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 of thepyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).
Possible beneficial effects
Lipoic acid has been the subject of numerous research studies and clinical trials:
- Prevent organ dysfunction
- Treat or prevent cardiovascular disease
- Accelerate chronic wound healing
- Reduce iron overload
- Prevent migraines
- Treat chronic diseases associated with oxidative stress
- Reduce inflammation
- Treat peripheral artery disease.
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. Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.
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. Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms. 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.
The antioxidant effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C and vitamin E deficiency. LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E. 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. 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. 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. Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.
Alpha Lipoic Acid (ALA) has a half life of 3 hours. Lipoic acid administration can significantly enhance biliary excretion of inorganic mercury in rat experiments, although it is not known if this is caused by chelation by lipoic acid or some other mechanism. Lipoic acid has the potential to cross the blood–brain barrier in humans, unlike DMSA and DMPS; its effectiveness, however, is heavily dependent on the dosage and frequency of application.
Medicinal differences between (R)-lipoic acid and (S)-lipoic acid
RLA is essential for life and aerobic metabolism, and RLA is the form biosynthesized in humans and other organisms studied so far. SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA were not bioequivalent. The first synthetic procedures appeared for RLA and SLA in the mid 1950s. 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. 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 mechanisms of action but evidence to date indicates RLA may be the eutomer (the nutritionally and therapeutically preferred form).
SLA is generally considered safe and nontoxic. It has been shown to be more toxic to thiamine deficient rats, but the mechanism or implications of this are not clear. SLA did not exist prior to chemical synthesis in 1952. 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. Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.
Lipoic acid in vivo seems primarily to induce the oxidative stress response rather than directly scavenge free radicals (see above). This effect is specific for RLA. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.
Clinical trials and approved uses
RLA is being used in a federally funded clinical trial for multiple sclerosis at Oregon Health and Science University. (R)-Lipoic acid is currently being used in two federally funded clinical trials at Oregon State University to test its effects in preventing heart disease and atherosclerosis. Alpha-lipoic acid is approved in Germany as a drug for the treatment of polyneuropathies, such as diabetic and alcoholic polyneuropathies, and liver disease.