Lipoic acid

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Not to be confused with linolenic acid or linoleic acid.
Lipoic acid
Names
IUPAC name
(R)-5-(1,2-dithiolan-3-yl)pentanoic acid
Other names
α-Lipoic acid (alpha lipoic acid); Thioctic acid; 6,8-Dithiooctanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.012.793 Edit this at Wikidata
KEGG
MeSH Lipoic+acid
  • InChI=1S/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1 checkY
    Key: AGBQKNBQESQNJD-SSDOTTSWSA-N checkY
  • InChI=1/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1
    Key: AGBQKNBQESQNJD-SSDOTTSWBZ
  • O=C(O)CCCC[C@H]1SSCC1
Properties
C8H14O2S2
Molar mass 206.32 g·mol−1
Appearance Yellow needle-like crystals
Soluble as sodium salt
Solubility in ethanol Soluble
Pharmacology
Pharmacokinetics:
30% (oral)[1]
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Lipoic acid (LA), also known as α-lipoic acid[2] and alpha lipoic acid (ALA)[3] is an organosulfur 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.[4] 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 the conjugate 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 the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).

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 mitochondria is used for this purpose.[5][6] 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 a radical SAM mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide.[7] 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 action of the enzyme lipoamidase.[8] 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.[9]

Lipoic acid-dependent complexes

2-Oxoacid dehydrogenase (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.[10][11] The geometry of the PDH E2 core is cubic in Gram-negative bacteria or dodecahedral in Eukaryotes and Gram-positive bacteria. It is interesting to note that the 2-OGDH and BCDH geometry is always cubic.[12] 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.[13] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[14]

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.

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.[15]

Biological sources and degradation

Lipoic acid is present in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[16] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. In addition, the amount of lipoic acid present in dietary sources is very low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.[17] As a result, all lipoic acid available as a supplement is chemically synthesized.

Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.[18] RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.[19][20][21]

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.[22] 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.[23][24][24][25][26][27] It is questionable whether food sources of RLA provide any measurable nutritional or therapeutic benefit due to the very low concentrations present.[28] Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiologic 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.[29] Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles.[30][31] It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2).[32]

Pharmacology and medical uses of free lipoic acid

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.[2] In Japan, LA is marketed primarily as a "weight loss" and "energy" supplement. The relationships between supplemental doses and therapeutic doses have not been clearly defined. Because lipoic acid is not an essential nutrient, no Recommended Daily Allowance (RDA) has been established. In Germany, LA is approved as a drug against diabetes comorbidities since 1966 and available by prescription.

According to the American Cancer Society, "there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer".[33]

For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for racemic R/S-LA.[34]

Effects

Lipoic acid has been the subject of numerous research studies and clinical trials:

  • For peripheral diabetic neuropathy, intravenous administration of alpha lipoic acid leads to a short-term improvement, but there is no good evidence of meaningful benefit when taking it by mouth.[35]
  • A review of literature by the Cochrane Dementia and Cognitive Improvement Group, using studies available from January 2008, did not find a any randomized controlled trials using lipoic acid to treat dementia. Due to the absence of evidence it could not support lipoic acid for the treatment of any form of Dementia.[36]

Because of 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 are not bioequivalent.[40] The original rationale for using (R/S)-lipoic acid as a nutritional supplement was that endogenous RLA was known to have biochemical properties like a B-vitamin (acting as a substrate or cofactor 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.[41][23][42][43][44] Injections of R/S-LA as low as 10–25 mg normalized daily urinary output and, in many cases, improved patient health. 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”.[45] 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 in essence stereospecific for RLA (100% active for RLA, 0% activity for SLA), so in essence it was believed SLA was 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.[46][47]

RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulphoraphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.[48][49] This stress response indirectly improves the antioxidant capacity of the cell.[2]

A recent human pharmacokinetic study of RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.[50] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.[50]

Adverse effects

Side effects of alpha lipoic acid may include headache, tingling or a "pins and needles" sensation, skin rash, or muscle cramps. There have been a few reports in Japan of a rare condition called insulin autoimmune syndrome in people using alpha lipoic acid.[citation needed][51] The condition causes hypoglycemia and antibodies directed against the body's own insulin without previous insulin therapy. The safety of alpha lipoic acid in pregnant or nursing women, children, or people with kidney or liver disease is unknown. The toxic dose in cats is much lower than that in humans or dogs [52] and produces hepatocellular toxicity.

Antioxidant and prooxidant effects of lipoic acid

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.[53][54][55][56][57][58][59] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[60]

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.[61][62] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[63] 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.[64][65]

The antioxidant effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C and vitamin E deficiency.[66] LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E.[63] 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.[2][28] 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.[67] 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.[68] 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. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.[2][28][48]

Metal chelation

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 whether this is caused by chelation by lipoic acid or some other mechanism.[69] 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.[70]

(R)-Lipoic acid (RLA, top) and (S)-lipoic acid (SLA, down). A 1:1 mixture (racemate) of (R)- and (S)-lipoic acid is called (RS)-lipoic acid or (±)-lipoic acid (R/S-LA).

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 are not bioequivalent.[40] The first synthetic procedures appeared for RLA and SLA in the mid-1950s.[71][72][73][74] 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. At the current time, 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.[75][76] 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).[68][77]

In general, SLA is 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.[47] SLA did not exist prior to chemical synthesis in 1952.[78][79] 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.[80] Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[81][82][83][84][85]

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.[2] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.[50]

Intravenous Delivery

In the 1970s, the first human clinical studies using alpha-lipoic acid (ALA) in the United States were carried out by Fredrick C. Bartter MD, Burton M. Berkson MD PhD, and associates from the National Institutes of Health. They administered intravenous ALA (racemic) to 79 people with acute and severe liver damage at various medical centers across the United States and 75 recovered full liver function Dr.'s Bartter and Berkson were subsequently appointed the FDA chief investigators for this therapeutic agent and Dr. Berkson went on to use it successfully for the treatment of chronic liver disease (viral hepatitis, autoimmune hepatitis, etc.)

Because of ALA's ability to modify gene expression by stabilizing NF kappa B transcription, Berkson started using intravenous ALA for the treatment of various cancers for which no effective treatments exist. In a 2006 publication, he and co-authors described the long-term survival of a patient with metastatic pancreatic cancer using ALA and various oral antioxidants.

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Further reading

  • Bartter F.C.; Berkson, B. M. G., J.; and Hiranaka, P. (1980) Treatment of Four Delayed-Mushroom-Poisoning Patients with Thioctic Acid., Baden-Baden, Koln, New York.
  • Berkson, B. M. (1979) Thioctic acid in treatment of hepatotoxic mushroom (Phalloides) poisoning. N Engl J Med 300, 371.
  • Berkson, B. M. (1980) Thioctic Acid in the Treatment of Poisoning with Alpha Amanitin, Baden-Baden, Koln, New York.
  • Berkson, B. M. (1998) Alpha-Lipoic Acid (Thioctic Acid): My Experience with this Outstanding Therapeutic Agent. Journal of Orthomolecular Medicine 13, 44-48.
  • Berkson, B. M. (1999) A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin (Munich) 94 Suppl 3, 84-9.
  • Berkson, B. M. (2000) A Triple Antioxidant Approach to the Treatment of Hepatitis C Using Alpha-Lipoic Acid (Thioctic Acid), Silymarin, Selenium, and other Fundamental Nutraceuticals. Clinical Practice of Alternative Medicine 1, 27-33.
  • Berkson, B. M., Rubin, D. M., and Berkson, A. J. (2006) The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integr Cancer Ther 5, 83-9.
  • Berkson BM, Rubin DM, Berkson AJ. Reversal of signs and symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone. Integr Cancer Ther. 2007 Sep;6(3):293-6.
  • Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther. 2009 Dec;8(4):416-22. doi: 10.1177/1534735409352082. Erratum in: Integr Cancer Ther. 2010 Jun;9(2):247.
  • Jane Higdon, "Lipoic Acid", Micronutrient Information Center, Linus Pauling Institute, Oregon State University
  • Packer, Lester; Patel, Mulchand S., eds. (2008). Lipoic acid: energy production, antioxidant activity and health effects. Boca Raton: CRC Press. ISBN 1-4200-4537-7. {{cite book}}: Invalid |ref=harv (help)
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