Talk:Lipoic acid

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

I appreciate the critical comments and I accept a few of your contentions. I will rephrase some of it to make the sentences more technically accurate. I think a more careful reading of the references and full text articles will prove that the references cited do not apply ONLY to “activity in oxoacid dehydrogenases” (endogenous RLA tested on isolated enzymes) or are there any “conflicting assertions”. I will review everything again line by line and ref by ref to verify this. Did you make this determination concerning “conflicting assertions “ from the titles? I have the full texts of each article cited and have studied them carefully. Most of the references cited refer specifically to supplementation (fed, injected or applied to culture medium) with equimolar amounts of either RLA and/or SLA compared to R/S-LA. Although some studies measured changes in PDH in response to the various concentrations and forms of LA, this in no way indicates these changes are without physiological relevance or that they apply only to “activity in oxoacid dehydrogenases.”

The cited references feature stereoselective or stereospecific mechanisms that likely have some relevance to humans consuming LA. At the very least this section and the references therein report the state of understanding of LA stereoselectivity in model systems. Unfortunately the number is somewhat limited because most studies have used only the racemic form. Several systems have shown no stereoselectivity and these should be added to future versions of the article as well.

I fail to see where I admit any such thing. Again, as stated above the references cited have more to do with supplemental LA and “pharmcological properties” than endogenous (oxoacid dehydrogenase) RLA, as you suggest. I believe that the references belong right where they are.

While it is believed that the pools of endogenous and exogenous RLA are distinct, cells do likely have the capacity to ligate some amount of supplemental RLA to the apoenzymes. The challenge has been to prove it because levels are so low it is difficult to detect and quantify. Early studies demonstrate that supplemented 35 S-LA incorporates into mitochondrial protein with a dependency of the amino acid content of the diet.

NAKAMURA T, KUSUNOKI T, KONISHI S, KATO H, MIBU A STUDIES ON THE METABOLISM OF ALPHA-LIPOIC ACID IN CHILDHOOD. 3. EFFECT OF DIETARY COMPOSITION AND ANBOLIC STEROID. J Vitaminol (Kyoto). 1965 Mar 10;11:60-7. PMID: 14327737

NAKAMURA T, KUSUNOKI T, KONISHI S, KATO H, MIBU A.STUDIES ON THE METABOLISM OF ALPHA-LIPOIC ACID IN CHILDHOOD. I. EFFECT OF PROTEIN AND AMINO ACID COMPOSITION IN THE DIET ON THE BIOSYNTHESIS OF PROTEIN-BOUND LIPOIC ACID. J Vitaminol (Kyoto). 1965 Mar 10;11:37-44. PMID: 14327733

It is still unclear if they are N-lipoylating proteins or S-lipoylated but they undoubtedly have some impact on the therapeutic mechanisms of action. The claim that the action of RLA on the activity of its native mitochondrial enzyme complexes has no effect on the pharmacology or cell function is without merit.

It is also known that applied RLA inhibits PDK1, one of the regulatory kinases of PDH which has the effect of increasing the activity of the enzyme, even if the RLA does not become ligated to the apoenzyme.

Korotchkina LG, Sidhu S, Patel MS. R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase. Free Radic Res. 2004 Oct;38(10):1083-92. PMID: 15512796

I agree the word” benefit” is somewhat leading and that the study does not measure “benefit”. It could be replaced by something more technically accurate such as “greater effect” in a given system but to the extent that any of these effects contribute to the nutritional or therapeutic efficacy of LA, then it is valid to claim it is beneficial. Recruitment of Glut4 is likely NOT the primary mechanism by which RLA functions but it likely makes some contribution (however transient) to the overall effects of LA.

If you compare only RLA and SLA your statement is accurate but if you compare one or the other of the enantiomers to equimolar amounts of R/S-LA then you can estimate the relative role of the inhibitory enantiomer in the model system, especially when concentrations of LA or another marker changing in response to LA are quantified. I will go back to each ref and verify that RLA was compared to R/S-LA and not just SLA alone and will revise accordingly.

Lower concentrations of RLA were found in a human endothelial cell line exposed to R/S-LA. When cells were exposed to RLA alone, it was more actively transported leading to higher intracellular concentrations than R/S-LA. This indicates a case of competitive inhibition of RLA transport by the SLA present in R/S-LA.

May JM, Qu ZC, Nelson DJ.Cellular disulfide-reducing capacity: an integrated measure of cell redox capacity. Biochem Biophys Res Commun. 2006 Jun 16;344(4):1352-9. Epub 2006 Apr 25. PMID: 16650819

In general, single enantiomers react in vivo differently than a racemic mixture. In most cases one enantiomer or the other either inhibits some specific activity or it has no effect. Theoretically a racemic mixture can have greater activity than a single enantiomer. Examples of the first two types are known that likely have physiological relevance and are sited in the references.

So far a theoretical argument for the third type of effect has been made for the possible superiority of R/S-LA but it is based on the assumption that DHLA is the more potent form of LA and functions primarily as a scavenger of free radicals which is in doubt.

Biewenga GP Haenen GRMM Groen BH Biewenga JE Van Grondelle R and Bast A (1997). "Combined non-enzymatic and enzymatic reduction favors bioactivation of racemic lipoic acid: an advantage of a racemic drug?". Chirality 9: 362–366.

Even the authors of the article raise the question as to whether or not this is true in vivo.

“Of course additional clinical studies are needed to substantiate that the racemic mixture has a superior therapeutic effect. To our knowledge, LA would then be the first drug of which-despite stereospecific enzymatic activation-the use of a racemic mixture is preferred over the use of one of the enantiomers.”

Bast A, Haenen GRMM. Lipoic acid a Multifunctional Antioxidant in Thiol Metabolism and Redox Regulation of Cellular Functions. Edited by Pompella A, Banhegyi G, Wellman-Rousseau M. IOS Press, Amsterdam, Berlin, Oxford, Tokyo, Washington DC. 2002, 230-7

In other cases it is unclear at which level (absorption, uptake, metabolism, tissue accumulation, etc) competitive inhibition is occurring but again testing the single enantiomers against the racemic mixture allows direct comparisons to be made amongst the different forms.

I would suggest that you are confusing the effects of glucose clearance with the therapeutic efficacy in treating symptoms of neuropathy. I agree R/S-LA is “just fine” for treatment of neuropathy but no form of LA has much effect on long term blood sugar regulation in humans or experimental animals. Acute increases in translocation of Glut 4 to the membrane was measured in the experiment cited and as stated above may have some contribution to the overall mechanisms of action of LA.

Most (but not all) of published clinical studies suggest that R/S-LA has proven therapeutic efficacy but there is no reason to believe it is the superior form for therapeutic or supplemental uses. It was due to the ready availability and low cost of R/S-LA relative to RLA and early successes clinically that so many studies have used only the racemic form. In addition it was believed that SLA was essentially inert and only present as isomeric balance. This is now known not to be true. While it is clear that SLA can make a contribution to the effects of LA when part of the racemic mixture and may in some cases exceed the activity of R/S-LA or RLA when administered alone, evidence to date does not support its daily use. In fact, the references cited do indicate that RLA is the eutomer of LA. If a single case of competitive inhibition of the unnatural SLA can be demonstrated with physiological relevance (and it has as shown in the May reference above) then this becomes the limiting criteria in vivo and it is best removed.

If only R/S-LA were available then I would eat it but since I have a choice the evidence to date supports the contention that when tested head to head RLA is superior to R/S-LA or SLA in most cases. This statement in no way negates all the clinical trials that have successfully utilized R/S-LA.--Sarah258 (talk) 20:55, 12 March 2010 (UTC)

I am disputing your interpretation of what you reference. The wiki article indicates that the pharmacological benefit of lipoic acid is due to regulation via NRF2. Therefore, enantiomer preference by anything other than NRF2 is irrelevant to pharmacology. It may be more appropriate in another section. The alternative mechanisms where enantiomers have an effect are speculative or extrapolated.

I don't doubt your expertise, but the article reads like an advert for R-lipoic acid as a dietary supplement. Perhaps you have a financial stake in R-lipoic acid use? You should avoid using speculative discussion in articles as factual support for statements. Perhaps you are reading the discussions and not looking at the data?

I have personally worked with the human lipoyltransferase, and I can tell you that it cannot ligate lipoic acid. Although lipoic acid activating enzyme has been characterized biochemically, evidence or its role in the cell is lacking. There are other mechanisms where lipoic acid could label mitochondria besides ligation to lipoyl domain (as you mention) and the references do not discriminate. Therefore I maintain my initial statement above. Qchristensen (talk) 18:49, 28 September 2010 (UTC)

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

While I appreciate the input, there seem to be some conflicting assertions on this subject. The 8+ references you cite for the specific activity of R lipoic acid are regarding activity in oxoacid dehydrogenases. You then go on to state that the biological activity of lipoic acid supplementation appears to be due to regulatory modulation (studies of which are very convincing). So, by your own admission I fail to see how oxoacid dehydrogenase activity has anything to do with pharmocological properties. As such I think some of this information belongs in another section (I'll work on it later). Qchristensen (talk) 03:55, 10 March 2010 (UTC)

Another blatant contridiction in this section: "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 [59]. This indicates that the most beneficial effects of RLA are inhibited when SLA is present." No, it means that R lipoic acid has a greater affect, not that the S enantiomer is inhibitory. Also, the study doesn't directly measure "benefit", were talking about recruitment of GLUT4 specifically. According to recent trials of lipoic acid supplementation to Diabetics, RS lipoic acid works fine (Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant {alpha}-lipoic acid: a meta-analysis. Diabet Med.2004; 21:114 -121.). Qchristensen (talk) 03:55, 10 March 2010 (UTC)

Quote from Article

Dihydrolipoic acid is able to regenerate (reduce) antioxidants Regenerate does not mean reduce, it means; Biology: to renew or restore (a lost, removed, or injured part). (Deragatory comments removed) Qchristensen (talk) 03:52, 20 March 2009 (UTC)

In response: To chemically reduce an oxidized compound, could be called regeneration. Basically bringing that compound back to its original electronegative state via a redox reaction.

Lipoate is know to have a protective role in maintaining glutathione levels —Preceding unsigned comment added by 59.167.170.232 (talk) 00:52, 19 December 2007 (UTC)

This may be true, but it may be due to a regulatory affect instead of the antioxidant properties of lipoic acid. The lipoic acid administered in this paper is not reduced. —Preceding unsigned comment added by Qchristensen (talk • contribs) 05:31, 9 April 2009 (UTC)

R LIPOIC ACID or thioctic acid

I've had arthritis for 30 years and I was on anti-inflammatories. I tried R Lipoic Acid and to my biggest surprise I could suddenly move my fingers in the morning without real pain and no longer have leg syndrome at night. I no longer use anti-inflammatories and swear by this supplement. My husband, who is diabetic, has now started this supplement. User Suzanne LeBlanc January 2, 2006

be careful because the mechanism of action of lipoic acid is not completely understood yet. It can have adverse affects. Please consult with a medical doctor. Qchristensen (talk) 05:36, 9 April 2009 (UTC)

Chelation therapy

Chelation therapy is certainly not the primary use of Lipoic acid! Lipoic acid is a very popular antioxidant supplement. While highly pushed by many people interested in taking nutritional supplements, its primarily weakness is the fact that its half-life is only about 20 minutes. Its extremely short half-life is what makes it ineffective to take as a supplement in anything other than a timed-released form.

Next on the gripe list, is the fact that many people believe that only the expensive R version is effective, while the L version is the form most commonly sold by vitamin suppliers.

this is not true, the cheaper version is a racemic mixture of R and S stereoisomers (it's typically R and S, although D and L are commonly used for sugars) Qchristensen (talk) 03:19, 10 March 2010 (UTC)

The half life is more like 3 hours, and should be a consideration in a low dose oral chelation protocol. Mercury toxic individuals can experience adverse reactions if this is not respected or with inappropriate doses. If the label doesn't say it's the R- form, then its manufactured as a racemic mixture. SomeNumpty 13:39, 10 October 2006 (UTC)

It would be most helpful if you used references for your arguments. I would like to see a reference for mercury chelation by lipoic acid. I think the literature has a lot of effects of lipoic acid, but little conclusive evidence as to the reason. There is even a paper concluding lipoic acid does not decrease mercury levels: Aposhian HV, Morgan DL, Queen HL, Maiorino RM, Aposhian MM. (2003). "Vitamin C, glutathione, or lipoic acid did not decrease brain or kidney mercury in rats exposed to mercury vapor". J Toxicol Clin Toxicol. 41 (4): 339–47. PMID 12870874. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) If an issue is controversial, the page should mention that or it shouldn't be mentioned at all. Qchristensen (talk) 05:33, 20 March 2009 (UTC)

Lipoic acid as a chelator

The article currently reads:

Neither DMSA nor MSM can cross the blood-brain barrier, which is why both lipoic acid and DMSA are used

But can MSM and Alpha Lipoic Acid be to remove mercury from the brain and body? I would think so given the context, but the information is not explicitly laid out in the article. Can anyone clarify? --Deepstratagem 08:48, 26 January 2006 (UTC)

Response to above "Question Regarding Chelation" Where did you get this information? There are a vast number of research articles written that state the exact opposite. -That DMSA and MSM do, infact cross the BB barrier. Kindly google this for yourself. Not to be confused with DMPS which is noted to be ineffective in crossing BB barrier. If you are looking for specific info regarding mercury removal from brain, study the ALA-DMSA protocol from Andy Cutler. [User:Cageykay] 3/26/06

You obviously didn't take the time to read my question. I got the information from the current article, and I'm asking whether it is accurate. The question is whether MSM can be used in combination with ALA to remove mercury from the brain and body. Are you going to answer it, or patronize me? --Deepstratagem 22:20, 26 March 2006 (UTC)

Deepstratagem, I read your question. Calm down, and tell me - are you quoting the "Lipoic Acid Article" itself? Or, could this possibly be from another article? I did state where you could look to get your answer. It will be detailed reading, but if it is not clear, then I invite you to e-mail me. Would be pleased to discuss further, Let's not continue wasting valauble space on Wikipedia. BTW, Deepstratagem, it's not my intent patronize you. Please don't take it as such. [User: CageyKay] 3/27/06

No problem. I thought I was clear in that the article in reference was the one corresponding to this discussion page. But it's not a waste to discuss it in Wikipedia if we are succint and it is related to the article; that way the article can be further improved. --Deepstratagem 08:52, 30 March 2006 (UTC)

I have removed the section of the article with the original quote cited above by Deepstrategem, sorry for any confusion. It is documented by four studies that MSM crosses the blood-brain barrier, so the article was incorrect (see MSM article). As to the question originally posed, after extensive review of the literature on MSM I have not come across any description of its use for removal of mercury, though I couldn't say that it is unable to do so. Prithason 01:00, 28 March 2006 (UTC)

I have added a reference supporting the fact that lipoic acid crosses the BBB barrier and the cell membrane. --Juliusllb 00:12, 12 February 2008 (UTC)

Assertion on the greater effectiveness of DMSA and DMPS as chelators has been removed because of the lack of references. I have added the fact that DMSA and DMPS cannot cross the BBB supported by two new references. I have also moved all this stuff to a new section on the possible use of lipoic acid as a chelator.--Juliusllb 20:28, 4 March 2008 (UTC)

DMSA and DMPS removed. Their purpose to contrast lipoic acid is inaccurate and unnecessary. References for copper and iron chelation would help. I'm guessing the evidence for protective chelation is poor. Qchristensen (talk) 07:03, 20 March 2009 (UTC)

I think mentioning the main difference between ALA compared to DMSA/DMPS is important. —Preceding unsigned comment added by Stengl (talk • contribs) 22:23, 23 April 2009 (UTC)

Thanks for adding the review article. The other reference (#40 currently) listed does not demonstrate that lipoic acid is a chelator. They speculate, but do not demonstrate. This could also be due to regulatory or redox affects of lipoic acid. If you have a reference that demonstrates chelation is responsible it would be helpful. Qchristensen (talk) 22:57, 5 May 2009 (UTC)

Missing subjects?

apparently it's a hot new thing in skin treatments. anyone knowledgable want to take a whack at that in the article? tej 14:09, 6 March 2006 (UTC)

1 what is the natural source of Lipoic Acid? 2 what are its traditional uses if any? 3 why is it in skin care products like the Skin Eternal range from Source Naturals? User: ceirius; 24 Aug'06 (moved down by Dirk Beetstra ^{T C} 07:24, 24 August 2006 (UTC), Ceirius, please use ~~~~ to sign your posts to talk pages)

1 lipoic acid is found in many living organisms, but at low abundance. Purification is impractical and although a (presumably failed) effort in Europe was made to grow it from bacteria, all available stuff is chemically synthesized. 2 The structure was elucidated in 1951, so that isn't a whole lot of tradition 3 Since it can reduce vitamin E in a test tube, and vitamin E is thought to be good for your skin, that is why. A mechanistic explanation for vitamin E and lipoic acid as beneficial supplements are lacking, but many scientists and consumers are convinced nonetheless. Perhaps I should add some of this to the article... Qchristensen (talk) 04:11, 20 March 2009 (UTC)

A toxicity section is really needed for this compound. This is also mentioned in the comments for the quality of this article. Qchristensen (talk) 05:34, 9 April 2009 (UTC)

Is it alpha-lipoic acid or alpha lipoic acid?

Is there an established 'correct' word form for alpha-lipoic acid? Both forms – alpha-lipoic acid and alpha lipoic acid – are used in the article and in the quoted references. Nunquam Dormio 17:22, 2 October 2007 (UTC)

I don't think it matters, but the people who named it used the dash: REED LJ et al. Crystalline alpha-lipoic acid...[PMID: 14854913] The alpha is really not necessary. They had many different ideas about the structure and it turned out that the "alpha" was the correct one. R-lipoic acid or S-lipoic acid or just lipoic acid works. Qchristensen (talk) 04:16, 20 March 2009 (UTC)

synthesize

After reading im not quite clear - what substances have to be part of a diet so the (human) body can sythesize lipoic acid? can the body build it "from scratch", given sulfur is present in some way? Or, well, not - Does it have to be part of the diet in its final form? This might be a useful addition to the article? --84.159.157.48 (talk) 13:08, 19 August 2008 (UTC)

The human body can synthesize lipoic acid, which is why it is not a vitamin. The genes for biosynthesis were first characterized at the Laboratory of John Cronan at the University of Illinois. The acyl chain comes from mitochondrial fatty acid biosynthesis and the sulfurs are from the lipoyl synthase protein itself. I guess I could add a section about biosynthesis...Qchristensen (talk) 04:19, 20 March 2009 (UTC)

Perhaps there is such a thing as too many References.

Perhaps some can be removed from the article, make it easyer to read. —Preceding unsigned comment added by 210.185.6.83 (talk) 22:23, 1 July 2010 (UTC)

This article needs help badly

I'm sorry to post this anonymously (I don't know crap about wikipedia) I want to say say that this is the most ridiculously over-written, over-wrought, and over-citationed article I've seen in almost 5 years of daily Wikipedia use. Seriously, 300+ references? Some sentences have over THIRTY superscript-numbers after them. Many of the sentences, even whole paragraphs, repeat themselves-sometimes VERBATIM. I have the feeling some alternative-health nut has descended onto the page to hype it up for some reason. The article has more technical information then a damned physician's deks reference, I mean what is this the American Journal of Nurtritional Biochemistry!? This article is crying for some ruthless editing. I wish I knew how. 97.123.108.92 (talk) 04:44, 11 October 2010 (UTC)

I agree that the long strings of superscript-numbers are not aesthetically pleasing, but hope that what ever editing will happen, no references are erased. Maybe a string of superscript-numbers exceeding for example 3 could be listed under one superscript-number? Probios (talk) 11:51, 12 October 2010 (UTC)