Lipoic acid

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
1200-22-2 (R) YesY
1077-28-7 (racemate) N
ChEBI CHEBI:30314 YesY
ChEMBL ChEMBL134342 YesY
ChemSpider 5886 YesY
DrugBank DB00166 YesY
4822
Jmol 3D model Interactive image
KEGG C16241 YesY
MeSH Lipoic+acid
PubChem 6112
UNII VLL71EBS9Z N
Properties
C8H14O2S2
Molar mass 206.32 g·mol−1
Appearance Yellow needle-like crystals
Melting point 46–48 °C (115–118 °F; 319–321 K)
Soluble as sodium salt
Solubility in ethanol Soluble
Pharmacology
A16AX01 (WHO)
Pharmacokinetics:
30% (oral)[1]
Related compounds
Related compounds
 Lipoamide
Asparagusic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Lipoic acid (LA), also known as α-lipoic acid and alpha lipoic acid (ALA) and thioctic acid is an organosulfur compound derived from octanoic acid. ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries.

Physical and chemical properties

Lipoic acid (LA), also known as α-lipoic acid[2] and alpha lipoic acid (ALA) and thioctic acid[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).

LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.

For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for R/S-LA.[4][5]

Biological function

"Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiologic conditions. 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).

Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.[6]

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.[7][8] The octanoate is transferred as a thioester of acyl carrier protein from fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase. Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase [9] As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.[10] Free lipoate can be used by some organisms as an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.[11]

Enzymatic Activity

Lipoic acid is cofactor for at least five enzyme systems. Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.

2-Oxoacid dehydrogenase transfer reactions occur by a similar mechanism in:

The most-studied of these is the pyruvate dehydrogenase 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.[12][13] 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.[14]

Lipoic acid serves as co-factor to the acetoin dehydrogenase complex 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. The individual components are free but it is sometimes incorrectly called a complex. In this system, 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 to synthesize serine from glycine. This system is part of plant photorespiration.[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 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.[23][24][24][25][26][27]

Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine. Certain bacteria can use lipoic acid as a carbon, sulfur, and energy source. An abundant intermediate in lipoic acid degradation was the shorter bisnorlipoic acid.[28][29] Although fatty acid degradation enzymes are likely involved, gene products responsible for use of lipoic acid as a sulfur source are unknown.

Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.[30] Lipoic acid is partially degraded by a variety of transformations, which can occur in various combinations. Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.[30] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.[31] Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.

Chemical synthesis of lipoic acid

SLA did not exist prior to chemical synthesis in 1952.[32][33] 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.[34] The first synthetic procedures appeared for RLA and SLA in the mid-1950s.[35][36][37][38] 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.[39][40] 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).[41][42]

Pharmacology of lipoic acid

Pharmacokinetics

A 2007 human pharmacokinetic study of sodium 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.[43] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.[43]

The various forms of LA are not bioequivalent.[34] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.[43]

The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.[44]

Pharmacodynamics

The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.[2] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[45] LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.[2][46] 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.[47] 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.[41] 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][46][48]

All 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.[49][50][51][52][53][54][55] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[56]

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][57] This stress response indirectly improves the antioxidant capacity of the cell.[2]

The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.[58][59]

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[60][61][62][63][64]

Uses

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 marketed 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.[65]

(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).

Clinical research

Clinical 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.[72] 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.

Other lipoic acids

Footnotes

  1. ↑ Teichert, J; Hermann, R; Ruus, P; Preiss, R (November 2003). "Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers". The Journal of Clinical Pharmacology 43 (11): 1257–67. doi:10.1177/0091270003258654. PMID 14551180.
  2. 1 2 3 4 5 6 Shay, KP; Moreau, RF; Smith, EJ; Hagen, TM (June 2008). "Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity". IUBMB Life 60 (6): 362–7. doi:10.1002/iub.40. PMID 18409172.
  3. ↑ Reljanovic, M; Reichel, G; Rett, K; Lobisch, M; et al. (September 1999). "Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): A two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy". Free Radical Research 31 (3): 171–9. doi:10.1080/10715769900300721. PMID 10499773.
  4. ↑ USP32-NF27. p. 1042.
  5. ↑ "Pharmacopeial Forum" 34 (5): 1209.
  6. ↑ Raddatz, G; Bisswanger, H (17 October 1997). "Receptor site and stereospecifity of dihydrolipoamide dehydrogenase for R- and S-lipoamide: A molecular modeling study". Journal of Biotechnology 58 (2): 89–100. doi:10.1016/S0168-1656(97)00135-1. PMID 9383983.
  7. ↑ Cronan, JE; Fearnley, IM; Walker, JE (29 August 2005). "Mammalian mitochondria contain a soluble acyl carrier protein". FEBS Letters 579 (21): 4892–6. doi:10.1016/j.febslet.2005.07.077. PMID 16109413.
  8. ↑ Jordan, SW; Cronan, JE, Jr. (1997). "A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria". Journal of Biological Chemistry 272 (29): 17903–6. doi:10.1074/jbc.272.29.17903. PMID 9218413.
  9. ↑ Cicchillo, RM; Booker, SJ (2005). "Mechanistic investigations of lipoic acid biosynthesis in E. coli: Both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide". Journal of the American Chemical Society 127 (9): 2860–1. doi:10.1021/ja042428u. PMID 15740115.
  10. ↑ Jiang, Y; Cronan, JE (2005). "Expression cloning and demonstration of Enterococcus faecalis lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase". Journal of Biological Chemistry 280 (3): 2244–56. doi:10.1074/jbc.+M408612200 (inactive 2015-01-14). PMID 15528186.
  11. ↑ Cronan, JE; Zhao, X; Jiang, Y (2005). Poole, RK, ed. "Function, attachment and synthesis of lipoic acid in Escherichia coli". Advances in microbial physiology. Advances in Microbial Physiology 50: 103–46. doi:10.1016/S0065-2911(05)50003-1. ISBN 9780120277506. PMID 16221579.
  12. ↑ Milne, JL; Wu, X; Borgnia, MJ; Lengyel, JS; et al. (2006). "Molecular structure of a 9-MDa icosahedral pyruvate dehydrogenase subcomplex containing the E2 and E3 enzymes using cryoelectron microscopy". Journal of Biological Chemistry 281 (7): 4364–70. doi:10.1074/jbc.M504363200. PMC 1647297. PMID 16308322.
  13. ↑ Murphy, GE; Jensen, GJ (2005). "Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes". Structure 13 (12): 1765–73. doi:10.1016/j.str.2005.08.016. PMID 16338405.
  14. ↑ Machado, RS; Clark, DP; Guest, JR (1992). "Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain". FEMS Microbiology Letters 79 (1–3): 243–8. doi:10.1111/j.1574-6968.1992.tb14047.x. PMID 1478460.
  15. ↑ Douce, R; Bourguignon, J; Neuburger, M; Rebeille, F (2001). "The glycine decarboxylase system: A fascinating complex". Trends in Plant Science 6 (4): 167–76. doi:10.1016/S1360-1385(01)01892-1. PMID 11286922.
  16. ↑ Durrani, AI; Schwartz, H; Nagl, M; Sontag, G (October 2010). "Determination of free [alpha]-lipoic acid in foodstuffs by HPLC coupled with CEAD and ESI-MS". Food Chemistry 120 (4): 38329–36. doi:10.1016/j.foodchem.2009.11.045.
  17. ↑ Reed, LJ (October 2001). "A trail of research from lipoic acid to alpha-keto acid dehydrogenase complexes". Journal of Biological Chemistry 276 (42): 38329–36. doi:10.1074/jbc.R100026200. PMID 11477096.
  18. ↑ Hermann, R; Niebch, G; Borbe, HO; Fieger, H; et al. (1996). "Enantioselective pharmacokinetics and bioavailability of different racemic formulations in healthy volunteers". European Journal of Pharmaceutical Sciences 4 (3): 167–74. doi:10.1016/0928-0987(95)00045-3.
  19. ↑ Teichert, J; Preiss, R (1997). High-performance Liquid Chromatography Methods for Determination of Lipoic and Dihydrolipoic Acid in Human Plasma. Methods in Enzymology 279. pp. 159–66. doi:10.1016/S0076-6879(97)79019-0. ISBN 9780121821807. PMID 9211267.
  20. ↑ Teichert, J; Preiss, R (October 1995). "Determination of lipoic acid in human plasma by high-performance liquid chromatography with electrochemical detection". Journal of Chromatography B 672 (2): 277–81. doi:10.1016/0378-4347(95)00225-8. PMID 8581134.
  21. ↑ Teichert, J; Preiss, R (November 1992). "HPLC-methods for determination of lipoic acid and its reduced form in human plasma". International Journal of Clinical Pharmacology, Therapy, and Toxicology 30 (11): 511–2. PMID 1490813.
  22. ↑ Biewenga, GP; Haenen, GR; Bast, A (September 1997). "The pharmacology of the antioxidant lipoic acid". General Pharmacology 29 (3): 315–31. doi:10.1016/S0306-3623(96)00474-0. PMID 9378235.
  23. ↑ Wada, M; Shigeta, Y; Inamori, K (September 1961). "A study on the metabolism of lipoic acid and lipoamide". Journal of Vitaminology 7 (3): 237–42. doi:10.5925/jnsv1954.7.237. PMID 14004240.
  24. 1 2 Oizumi, J; Hayakawa, K (July 1989). "Liberation of lipoate by human serum lipoamidase from bovine heart pyruvate dehydrogenase". Biochemical and Biophysical Research Communications 162 (2): 658–63. doi:10.1016/0006-291X(89)92361-9. PMID 2502979.
  25. ↑ Saito, J (1960). "[The conversion of thioctamide to thioctic acid in biological systems. I. The thioctic active substances in rabbit serum after administration of thioctamide]". Vitamin (in Japanese) 21 (3): 359–63.
  26. ↑ Backman-Gullers, B; Hannestad, U; Nilsson, L; Sorbo, B (October 1990). "Studies on lipoamidase: Characterization of the enzyme in human serum and breast milk". Clinica Chimica Acta 191 (1–2): 49–60. doi:10.1016/0009-8981(90)90057-Y. PMID 2127386.
  27. ↑ Garganta, CL; Wolf, B (August 1990). "Lipoamidase activity in human serum is due to biotinidase". Clinica Chimica Acta 189 (3): 313–25. doi:10.1016/0009-8981(90)90313-H. PMID 2225462.
  28. ↑ Shih, JC; Rozo, ML; Wright, LD; McCormick, DB (February 1975). "Characterization of the growth of Pseudomonas putida LP on lipoate and its analogues: Transport, oxidation, sulphur source, and enzyme induction" (PDF). Microbiology 86 (2): 217–27. doi:10.1099/00221287-86-2-217. PMID 1089758.
  29. ↑ Mansilla, MC; de Mendoza, D (February 1997). "L-cysteine biosynthesis in Bacillus subtilis: Identification, sequencing, and functional characterization of the gene coding for phosphoadenylylsulfate sulfotransferase". Journal of Bacteriology 179 (3): 976–81. PMC 178787. PMID 9006060.
  30. 1 2 Schupke, H; Hempel, R; Peter, G; Hermann, R; et al. (June 2001). "New metabolic pathways of alpha-lipoic acid". Drug Metabolism and Disposition 29 (6): 855–62. PMID 11353754.
  31. ↑ Teichert, J; Hermann, R; Ruus, P; Preiss, R (November 2003). "Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers". Journal of Clinical Pharmacology 43 (11): 1257–67. doi:10.1177/0091270003258654. PMID 14551180.
  32. ↑ Hornberger, CS; Heitmiller, RF; Gunsalus, IC; Schnakenberg, GHF; et al. (1953). "Synthesis of DL—lipoic acid". Journal of the American Chemical Society 75 (6): 1273–7. doi:10.1021/ja01102a003.
  33. ↑ Hornberger, CS; Heitmiller, RF; Gunsalus, IC; Schnakenberg, GHF; et al. (1952). "Synthetic preparation of lipoic acid". Journal of the American Chemical Society 74 (9): 2382. doi:10.1021/ja01129a511.
  34. 1 2 Kleeman, A; Borbe, HO; Ulrich, H (1991). "Thioctic Acid-Lipoic Acid". In Borbe, HO; Ulrich, H. Thioctsäure: Neue Biochemische, Pharmakologische und Klinische Erkenntnisse zur Thioctsäure [Thioctic Acid. New Biochemistry, Pharmacology and Findings from Clinical Practice with Thioctic Acid]. Symposium at Wiesbaden, DE, 16–18 February 1989. Frankfurt, DE: Verlag. pp. 11–26. ISBN 9783891191255.
  35. ↑ Fontanella, L (1955). "Preparation of optical antipodes of alpha-lipoic acid". Il Farmaco; edizione scientifica 10 (12): 1043–5. PMID 13294188.
  36. ↑ Walton, E; Wagner, AF; Bachelor, FW; Peterson, LH; et al. (1955). "Synthesis of (+)-lipoic acid and its optical antipode". Journal of the American Chemical Society 77 (19): 5144–9. Bibcode:1955JAChS..77.1678G. doi:10.1021/ja01624a057.
  37. ↑ Acker, DS; Wayne, WJ (1957). "Optically active and radioactive α-lipoic acids". Journal of the American Chemical Society 79 (24): 6483–6487. doi:10.1021/ja01581a033.
  38. ↑ Deguchi, Y; Miura, K (June 1964). "Studies on the synthesis of thioctic acid and its related compounds. XIV. Synthesis of (+)-thioctamide". Yakugaku Zasshi 84: 562–3. PMID 14207116.
  39. ↑ Lang, G (1992). In Vitro Metabolism of a-Lipoic Acid Especially Taking Enantioselective Bio-transformation into Account (Ph.D. thesis). Münster, DE: University of Münster.
  40. ↑ US patent 5281722, Blaschke, G; U Scheidmantel & H Bethge et al., "Preparation and use of salts of the pure enantiomers of alpha-lipoic acid", issued 1994-01-25, assigned to DeGussa.
  41. 1 2 Carlson, DA; Young, KL; Fischer, SJ; Ulrich, H. "Ch. 10: An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Human Subjects". Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. pp. 235–70. In Packer & Patel 2008.
  42. ↑ Packer, L; Kraemer, K; Rimbach, G (October 2001). "Molecular aspects of lipoic acid in the prevention of diabetes complications". Nutrition (Burbank, CA) 17 (10): 888–95. doi:10.1016/S0899-9007(01)00658-X. PMID 11684397.
  43. 1 2 3 Carlson, DA; Smith, AR; Fischer, SJ; Young, KL; et al. (December 2007). "The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects" (PDF). Alternative Medicine Review 12 (4): 343–51. PMID 18069903.
  44. ↑ Hill, AS; Werner, JA; Rogers, QR; O'Neill, SL; et al. (April 2004). "Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats". Journal of Animal Physiology and Animal Nutrition 88 (3–4): 150–6. doi:10.1111/j.1439-0396.2003.00472.x. PMID 15059240.
  45. ↑ Packer, L; Witt, EH; Tritschler, HJ (August 1995). "Alpha-lipoic acid as a biological antioxidant". Free Radical Biology and Medicine 19 (2): 227–50. doi:10.1016/0891-5849(95)00017-R. PMID 7649494.
  46. 1 2 Shay, KP; Moreau, RF; Smith, EJ; Smith, AR; et al. (October 2009). "Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential". Biochimica et Biophysica Acta 1790 (10): 1149–60. doi:10.1016/j.bbagen.2009.07.026. PMC 2756298. PMID 19664690.
  47. ↑ Haenen, GRMM; Bast, A (1991). "Scavenging of hypochlorous acid by lipoic acid". Biochemical Pharmacology 42 (11): 2244–6. doi:10.1016/0006-2952(91)90363-A. PMID 1659823.
  48. 1 2 Shay, KP; Shenvi, S; Hagen, TM. "Ch. 14 Lipoic Acid as an Inducer of Phase II Detoxification Enzymes Through Activation of Nr-f2 Dependent Gene Expression". Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. pp. 349–71. In Packer & Patel 2008.
  49. ↑ Arnér, ES; Nordberg, J; Holmgren, A (August 1996). "Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase". Biochemical and Biophysical Research Communications 225 (1): 268–74. doi:10.1006/bbrc.1996.1165. PMID 8769129.
  50. ↑ Biaglow, JE; Ayene, IS; Koch, CJ; Donahue, J; et al. (April 2003). "Radiation response of cells during altered protein thiol redox". Radiation Research 159 (4): 484–94. doi:10.1667/0033-7587(2003)159[0484:RROCDA]2.0.CO;2. PMID 12643793.
  51. ↑ Haramaki, N; Han, D; Handelman, GJ; Tritschler, HJ; et al. (1997). "Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid". Free Radical Biology and Medicine 22 (3): 535–42. doi:10.1016/S0891-5849(96)00400-5. PMID 8981046.
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