ALPHA-LIPOIC ACID
Also known as thioctic acid, alpha-lipoic acid is a naturally occurring compound that is synthesized by plants and animals, including humans. Alpha-lipoic acid contains two sulfur molecules that can be oxidized or reduced. This feature allows alpha-lipoic acid to function as a cofactor for several important enzymes as well as a potent antioxidant. Only the R-isomer of alpha-lipoic acid is synthesized naturally. Conventional chemical synthesis of alpha-lipoic acid results in a 50/50 (racemic) mixture of the two optical isomers, R-alpha-lipoic acid and S-alpha-lipoic acid. (1). In the text that follows, the term "alpha-lipoic acid" refers to racemic alpha-lipoic acid, while "R-alpha-lipoic acid" or "S-alpha-lipoic acid" refers to the specific isomer.
FUNCTION
Enzyme cofactor
R-Alpha-lipoic acid is normally bound to proteins by linkage of its carboxyl (COOH) group to a lysine residue in the protein. In its protein bound form, lipoamide, R-alpha-lipoic acid is a required cofactor for several multi-enzyme complexes that catalyze critical energy metabolism reactions inside the mitochondria. The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA, an important substrate for energy production, via the citric acid cycle. The alpha-ketoglutarate dehydrogenase complex catalyzes another important citric acid cycle reaction. The branched-chain alpha-keto acid dehyrogenase complex catalyzes the metabolism of three amino acids, leucine, isoleucine, and valine, also known as branched-chain amino acids. The glycine cleavage system is a multi-enzyme complex that catalyzes the formation of 5,10 methylene tetrahydrofolate, an important cofactor in nucleic acid synthesis (2).
Antioxidant
When large amounts of free alpha-lipoic acid are available (e.g., with supplementation), alpha-lipoic acid is also able to function as an antioxidant (3). Alpha-dihydrolipoic acid (DHLA) is the reduced form of alpha-lipoic acid, and is the only form that functions directly as an antioxidant (structure). Free alpha-lipoic acid is rapidly taken up by cells and reduced to DHLA intracellularly. Because DHLA is also rapidly eliminated from cells, the extent to which its antioxidant effects can be sustained remain unclear. Although only DHLA functions directly as an antioxidant, alpha-lipoic acid may have indirect antioxidant effects (4).
Scavenging free radicals: DHLA may prevent oxidative damage by interacting with potentially damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS) (5).
Regenerating other antioxidants: When an antioxidant like vitamin C neutralizes a free radical, it becomes oxidized itself, and is not able to neutralize other free radicals until it has been reduced or regenerated. DHLA is a potent reducing agent, and has the capacity to regenerate a number of oxidized antioxidants to their active antioxidant forms (diagram). Specifically, DHLA is capable of reducing the oxidized forms of vitamin C, glutathione, and coenzyme Q10, which are able to regenerate oxidized alpha-tocopherol (vitamin E), forming an antioxidant network. DHLA can be regenerated from alpha-lipoic acid through the activity of enzymes present in cells (1).
Chelation of metal ions: Certain free metal ions like iron and copper can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals. Both alpha-lipoic acid and DHLA may chelate or bind metal ions in a way that prevents them from generating free radicals (1). At present, this property has only been demonstrated in the test tube and in extracellular fluids.
Increasing intracellular glutathione levels: Glutathione is an important water-soluble antioxidant that is synthesized from the sulfur-containing amino acid cysteine. The availability of cysteine inside a cell determines its rate of glutathione synthesis. DHLA has been found to increase the uptake of cysteine by cells in culture, leading to increased glutathione synthesis (1). Although increases in intracellular DHLA are short-lived, DHLA may also improve intracellular antioxidant capacity by inducing glutathione synthesis.
Repair of oxidative damage: The protein, alpha1-antiprotease, is an inhibitor of the enzyme elastase. Oxidation inactivates alpha1-antiprotease, leading to increased activity of elastase and degradation of elastin in the lungs, a process that has been implicated in chronic obstructive pulmonary disease (COPD). In the test tube, DHLA can act as a reducing factor for the enzyme, peptide methionine sulfoxide reductase (PMSR), which can reduce and reactivate oxidized alpha1-antiprotease (6). Whether alpha-lipoic acid contributes to the repair of oxidized proteins in living organisms remains to be determined.
Regulation of gene transcription
The protein, NF-kappaB (NF-kB), is known as a transcription factor because it is able to bind to DNA and affect the rate of transcription of certain genes that have NF-kB binding sites. NF-kB plays an important role in regulating genes related to inflammation and the pathology of a number of diseases, including atherosclerosis, cancer, and diabetes (2). Physiologically relevant concentrations of alpha-lipoic acid have been found to inhibit the activation of NF-kB when added to cells in culture (7).
AP-1 is another transcription factor that can be affected by both reactive oxygen species (ROS) and certain antioxidants within cells. Treating cells in culture with DHLA has been found to inhibit the activity of AP-1 by decreasing the expression of the gene for c-fos, one of the proteins that makes up the functional AP-1 complex (8).
DEFICIENCY
a-Lipoic acid deficiency has not been described, suggesting that humans are able to synthesize enough to meet their needs for enzyme cofactors. Increased destruction of the cofactor form of alpha-lipoic acid may underlie the pathology of some diseases. In arsenic toxicity, arsenic can form a complex with alpha-lipoic acid in dehydrogenase enzymes, leaving it inactive (3). Circulating antibodies to lipoamide-containing enzyme subunits have been isolated in patients with an autoimmune liver disease known as primary biliary cirrhosis (9).
DISEASE PREVENTION
Aging
Mitochondria are cellular organelles that oxidize dietary fuels (proteins, fats, and carbohydrates) to a usable form of energy, adenosine triphosphate (ATP). Free radicals or reactive oxygen species (ROS) are also produced by mitochondria as a byproduct of energy production. If not neutralized by antioxidants, ROS may damage mitochondria over time, causing them function less efficiently and to generate more damaging ROS in a self-perpetuating cycle. Many experts feel that this deterioration in mitochondrial function is directly related to functional declines in aging and age-related diseases (10). In aging rats, short-term dietary supplementation with R-alpha-lipoic acid has been found to decrease mitochondrial ROS production and improve mitochondrial function (11, 12). A series of studies in aged rats found that combined dietary supplementation of R-alpha-lipoic acid and acetyl-L-carnitine improved mitochondrial energy metabolism, decreased oxidative stress, increased physical activity, and improved measures of short-term memory (13, 14). Acetyl-L-carnitine is a supplemental form of L-carnitine, an amino acid derivative that plays a crucial role in mitochondrial energy metabolism. (See L-carnitine for more information.) While these findings are very encouraging, the researchers caution that these studies used relatively high doses of the compounds for only for one month. It is not yet known whether taking relatively high doses of R-alpha-lipoic acid and acetyl-L-carnitine will benefit aging rats in the long-term or will have similar effects in humans. Clinical trials of a combination supplement of alpha-lipoic acid and acetyl-L-carnitine in humans currently underway, but the results of these trials are not yet available for evaluation.
For more information about aging and oxidative stress, see the article, Aging with Dr. Tory Hagen, in the Fall/Winter 2000 LPI Newsletter.
DISEASE TREATMENT
Diabetes mellitus
Chronically elevated blood glucose levels are the hallmark of diabetes mellitus. Type I diabetes is also known as juvenile-onset or insulin-dependent diabetes mellitus (IDDM) because it often develops in childhood or adolescence, and insulin therapy is required to control blood glucose levels. Type II diabetes is also known as adult-onset diabetes or non-insulin-dependent diabetes mellitus (NIDDM) because it is more common in older adults and may not require insulin therapy. However, type II diabetes may also develop in children and adolescents, and its treatment may eventually require insulin therapy. Pharmacologic doses of alpha-lipoic acid (i.e., many times higher than the amount a person could synthesize or obtain from foods) have been prescribed to treat diabetic patients in Germany since the late 1960's (4). Below is a summary of research on the use of alpha-lipoic acid supplementation to treat diabetes and its complications.
Insulin sensitivity: In type II diabetes, elevated blood glucose levels result from insulin resistance rather than a lack of insulin, and a number of treatments have been aimed at improving insulin sensitivity. There is limited evidence that high doses of alpha-lipoic acid can improve insulin sensitivity in individuals with type II diabetes. Intravenous infusions of 600 mg (15) and 1,000 mg (16) of alpha-lipoic acid to type II diabetics, improved insulin sensitivity by 27% and 51%, respectively compared to a placebo. An uncontrolled study of 20 type II diabetics found that oral administration of 1,200 mg of alpha-lipoic acid for 4 weeks significantly improved measures of glucose metabolism (17), and a placebo-controlled study of 72 type II diabetics found that oral alpha-lipoic acid at doses of 600 mg/day, 1,200 mg/day or 1,800 mg/day for 4 weeks improved insulin sensitivity by 25% (18). However, there were no significant differences between the three doses of alpha-lipoic acid tested. All of these studies were conducted using racemic alpha-lipoic acid. Data from animal studies suggests that the R-isomer may be more effective in improving insulin sensitivity than the S-isomer (19, 20), but this possibility has not been tested in any published human trials.
Oxidative stress: A number of studies in individuals with diabetes (type I and type II) indicate that they are under increased oxidative stress, a condition that is believed to contribute to the vascular and neurologic complications of diabetes. Although alpha-lipoic acid supplementation has been found to reduce measures of oxidative stress in animal models of diabetes, evidence that alpha-lipoic acid reduces oxidative stress in humans with diabetes is limited. In a non-randomized cross-sectional study, 33 patients with type I or type II diabetes who had been taking 600 mg/day of alpha-lipoic acid orally for at least 3 months had lower levels of plasma lipid peroxidation than did 74 diabetics who did not take alpha-lipoic acid (21). An intervention trial in 10 diabetic patients found that plasma lipid peroxides were significantly lower after taking 600 mg/day of alpha-lipoic acid orally for 60 days compared to baseline (22). The NF-kB transcription factor is known to increase the transcription of genes related to inflammation in response to increased oxidative stress. Oral alpha-lipoic acid supplementation (600 mg/day) has been found to decrease NF-kB activation in the white blood cells of type I diabetics (23) and patients with diabetic nephropathy (kidney damage) (24). The formation of advanced glycation end products (AGEP) also leads to glucose-mediated damage in diabetes. Alpha-lipoic acid has been found to prevent the formation of AGEP in the test tube (25).
Diabetic peripheral neuropathy: Over one third of diabetics develop peripheral neuropathy, a type of nerve damage that may result in decreased sensitivity, numbness, and pain, particularly in the lower extremities. In addition to the pain and disability caused by diabetic neuropathy, it is a leading cause of lower limb amputation in diabetics (26). The results of several large randomized controlled trials indicate that maintaining blood glucose at near normal levels is the most important step in decreasing the risk of diabetic neuropathy (27, 28). However, such intensive blood glucose control may not be achievable in all diabetic patients. Oxidative stress has been implicated in the pathology of diabetic neuropathy, and alpha-lipoic acid is approved for the treatment of diabetic neuropathy in Germany (1).
At least 15 clinical trials have examined the effect of alpha-lipoic acid treatment on symptoms of diabetic neuropathy with mixed results, especially in smaller studies (29). Modest benefits have been observed in several large multi-center trials. More than 300 type II diabetics with symptomatic peripheral neuropathy were randomly assigned to intravenous treatment with 100 mg/day, 600 mg/day, or 1,200 mg/day of alpha-lipoic acid or placebo for 3 weeks (30). Symptom scores were significantly improved in those that received intravenous infusions of at least 600 mg/day of alpha-lipoic acid compared to placebo. A subsequent multi-center trial randomly assigned 509 type II diabetics with symptomatic peripheral neuropathy to one of three treatments: 1) 600 mg/day of intravenous alpha-lipoic acid for 3 weeks followed by 1,800 mg/day of oral alpha-lipoic acid (600 mg, 3 times/day) for 6 months, 2) 600 mg/day of intravenous alpha-lipoic acid for 3 weeks followed by oral placebo for 6 months, or 3) intravenous placebo for 3 weeks followed by oral placebo for 6 months (31). Although symptom scores did not differ significantly from baseline in any of the groups, assessments of sensory and motor deficits by trained physicians were significantly improved after 3 weeks of intravenous alpha-lipoic acid therapy and non-significantly improved at the end of 6 months of oral alpha-lipoic acid therapy. A smaller randomized controlled trial examined the effect of long-term oral alpha-lipoic acid supplementation on the results of electrophysiologic nerve conduction studies in 65 diabetic patients with symptomatic peripheral neuropathy (32). After two years of follow up, those who took either 600 mg/day or 1,200 mg/day of alpha-lipoic acid orally showed significant improvements in 3 out of 4 nerve conduction assessments compared to those who took placebo.
Overall, the available research suggests that oral doses of at least 600 mg/day of alpha-lipoic acid may offer some benefit in the alleviation of neuropathic symptoms and deficits, especially when used in conjunction with effective treatment aimed at normalizing blood glucose levels.
Vascular complications: The inner lining of blood vessels, known as the endothelium, plays an important role in preventing vascular disease. Endothelial function in individuals with diabetes (type I and type II) is often impaired, and diabetics are at increased risk for vascular disease. Several small preliminary studies in humans have examined the effect of alpha-lipoic acid administration on endothelial function. In one study, intra-arterial infusions of alpha-lipoic acid improved endothelium-dependent vasodilation (blood vessel relaxation) in 39 diabetic patients, but not in 11 healthy controls (33). Oral supplementation of 1,200 mg/day of alpha-lipoic acid for 6 weeks improved a measure of capillary perfusion in the fingers of 8 diabetic patients with peripheral neuropathy (34). In an uncontrolled, non-randomized study of 84 diabetic patients, plasma thrombomodulin levels, a marker of compromised endothelial function, decreased significantly in the 35 diabetics that took 600 mg/day of alpha-lipoic acid orally over 18 months, while thrombomodulin levels increased significantly in those that did not take alpha-lipoic acid over the same period (35). While the results of these small, uncontrolled trials are encouraging, long-term placebo-controlled studies are needed before it can be determined whether alpha-lipoic acid supplementation can reduce the risk of vascular complications in individuals with diabetes.
SOURCES
Biosynthesis
Alpha-lipoic acid can be synthesized by plants and animals. The biosynthetic pathway for alpha-lipoic acid is not known, but it appears to be synthesized in the mitochondria from an 8-carbon fatty acid and elemental sulfur (5). It is currently unclear whether synthesis by normal gastrointestinal bacteria is a significant source of alpha-lipoic acid in humans. Biosynthesis does not appear to result in large amounts of circulating free alpha-lipoic acid, the form that is likely to function as an antioxidant (3).
Food sources
Most alpha-lipoic acid in food is derived from lipoamide-containing enzymes and is bound to the amino acid, lysine (lipoyllysine). Animal tissues that are rich in lipoyllysine include kidney, heart, and liver, while plant sources that are rich in lipoyllysine include spinach, broccoli, and tomatoes. Somewhat lower amounts of lipoyllysine have been measured in peas, brussel sprouts, and rice bran (36). Digestive enzymes do not break the bond between alpha-lipoic acid and lysine very effectively. Thus, it has been hypothesized that most dietary alpha-lipoic acid is absorbed as lipoyllysine, and free alpha-lipoic acid has not been detected in the circulation of humans who are not taking alpha-lipoic acid supplements (3). Although alpha-lipoic acid is found in a wide variety of foods from plant and animal sources, quantitative information on the alpha-lipoic acid content of food is limited. In the table below, the alpha-lipoic acid content of some foods was calculated from measurements of lipoyllysine in freeze-dried food samples (36).
|
Food |
Lipoyllysine
(mg/g dry weight) |
Serving |
Alpha-lipoic acid*/serving
(mcg)# |
| Beef kidney |
2.6 |
3 ounces (85 g) |
32 |
| Beef heart |
1.5 |
3 ounces (85 g) |
19 |
| Beef liver |
0.9 |
3 ounces (85 g) |
14 |
| Spinach |
3.2 |
1 cup raw (30 g) |
5 |
| Broccoli |
0.9 |
1 cup raw (71 g) |
4 |
| Tomato |
0.6 |
1 medium (123 g) |
3 |
| Peas |
0.4 |
1 cup raw (145 g) |
7 |
| Brussel sprouts |
0.4 |
1 cup raw (88 g) |
3 |
| Rice bran |
0.2 |
1 cup (118 g) |
11 |
| Egg yolk |
0.05 |
1 large (17 g) |
0.3 |
*Lipoyllysine x 0.62 = alpha-lipoic acid (1)
#1,000 micrograms (mcg) = 1 milligram (mg)
Supplements
Supplemental doses of alpha-lipoic acid are hundreds of times higher than the amounts that can be obtained from food, and should be considered pharmacologic rather than physiologic doses. Alpha-lipoic acid is available by prescription in Germany, where it is approved for the treatment of diabetic and alcoholic neuropathies and alcoholic liver disease. It is available in the U.S. without a prescription as a dietary supplement (37). Until recently, alpha-lipoic acid was only available as a racemic mixture of R- and S-alpha-lipoic acid, which may also be labeled as D-,L-alpha-lipoic acid. Preparations containing only R-alpha lipoic acid are now available in the U.S., but they are more expensive than racemic mixtures of R-,S-alpha-lipoic acid.
Alpha-lipoic acid from supplements is rapidly absorbed, rapidly metabolized, and rapidly cleared from plasma and tissues, suggesting that it should be taken in divided doses throughout the day, rather than in a single daily dose. The bioavailability of an orally administered dose of 200 mg is about 20-30% that of an intravenous dose (38, 39). Recommendations for the use of racemic alpha-lipoic acid as an antioxidant range from 50 mg/day to 400 mg/day. In the only published study to examine the in vivo antioxidant effects of alpha-lipoic acid in healthy humans, 600 mg/day for 4 months significantly decreased several biomarkers of oxidative stress compared to baseline (40). However, the antioxidant effects of lower doses have not been well studied in humans.
Racemic vs. R-alpha-lipoic acid: There is evidence that the two optical isomers of alpha-lipoic acid have different biological activities. R-alpha-lipoic acid occurs naturally in plants and animals and is the only form that functions as a cofactor for mitochondrial enzymes (see Function). Chemical synthesis of alpha-lipoic acid results in a 50/50 or racemic mixture of S-alpha-lipoic acid and R-alpha-lipoic acid. Within the mitochondria, R-alpha-lipoic acid is reduced to DHLA, the more potent antioxidant, 28 times faster than S-alpha-lipoic acid. However, in the cytosol S-alpha-lipoic acid is reduced to DHLA twice as fast as R-alpha-lipoic acid. One study in humans found R-alpha-lipoic acid to be more bioavailable than S-alpha-lipoic acid when taken orally (38). R-lipoic acid was more effective than S-lipoic acid in enhancing insulin-stimulated glucose transport and metabolism in insulin-resistant rat skeletal muscle (19), and R-alpha-lipoic acid was more effective than racemic alpha-lipoic acid and S-alpha-lipoic acid in preventing cataracts in rats (41). Almost all studies of alpha-lipoic acid supplementation in humans have been performed using racemic alpha-lipoic acid. At present, it is not known whether R-alpha-lipoic acid is more effective as an antioxidant than racemic lipoic acid when taken by humans in pharmacologic doses.
SAFETY
Toxicity
In general, alpha-lipoic acid doses of 600 mg/day have been well tolerated. Doses as high as 1,200 mg/day (600 mg, 2 times/day) for 2 years and 1,800 mg/day (600 mg, 3 times/day) for 3 weeks did not result in adverse effects when given to patients with diabetic neuropathy under medical supervision. There are no reports of toxicity from alpha-lipoic acid overdose in humans. In individuals with diabetes and/or impaired glucose tolerance, alpha-lipoic acid supplementation may lower blood glucose levels. Individuals on diabetic medications should monitor blood glucose levels. Diabetic medication doses may need to be adjusted to avoid hypoglycemia. Because controlled safety studies in pregnant and lactating women are not available, the use of alpha-lipoic acid supplements by pregnant or breastfeeding women is not recommended (37).
Drug Interactions
Alpha-lipoic acid supplements may affect the optimal dose of medications used to control blood glucose in diabetics. Individuals on such hypoglycemic agents should monitor their blood glucose levels and consult their health care provider for dosage adjustments if necessary to prevent hypoglycemia (37).
SUMMARY
- R-alpha-lipoic acid functions as a critical cofactor in several important enzymes related to energy metabolism. More information
- Alpha-lipoic acid deficiency has not been described, suggesting that humans are able to synthesize enough to meet their needs for enzyme cofactors. More information
- In doses achievable through supplementation, alpha-lipoic acid can act as an antioxidant. More information
- Controlled clinical trials indicate that 600 mg/day of racemic alpha-lipoic acid may reduce symptoms and neurological deficits associated with diabetic neuropathy. More information
- Although recent studies in rats suggest that supplementation with the combination of R-alpha-lipoic acid and acetyl-L-carnitine may be beneficial in preventing age-related declines in energy metabolism and memory, it is not known whether supplementation with these compounds will help prevent such age-related declines in humans. More information
- Although generally well tolerated, alpha-lipoic acid supplementation may affect the optimal dose of medications used to control blood glucose in diabetics or precipitate hypoglycemia. More information
REFERENCES
Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Assistant Professor, Dept. of Biochemistry and Biophysics
Oregon State University
Last updated 07/23/2003 Copyright 2002-2003 by The Linus Pauling Institute