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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.<ref name= "Shay08"/> Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.<ref name="Packer1995">{{cite journal |doi= 10.1016/0891-5849(95)00017-R |pmid= 7649494 |last1= Packer |first1= L |last2= Witt |first2= EH |last3= Tritschler |first3= HJ |title= Alpha-lipoic acid as a biological antioxidant |journal= [[Free Radical Biology and Medicine]] |volume= 19 |issue= 2 |date= August 1995 |pages= 227–50}}</ref> 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.<ref name= "Shay08"/><ref name="ReferenceC">{{cite journal |pmid= 19664690 |pmc= 2756298 |last1= Shay |first1= KP |doi= 10.1016/j.bbagen.2009.07.026 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Smith |first4= AR |last5= Hagen |first5= TM |display-authors= 4 | title = Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential |journal= [[Biochimica et Biophysica Acta (BBA) - General Subjects]] |volume= 1790 |issue= 10 |date= October 2009 |pages= 1149–60}}</ref> 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 and for lowering the redox activities of unbound iron and copper.<ref>{{cite journal |last1= Haenen |first1= GRMM |last2= Bast |first2= A |year= 1991 |title= Scavenging of hypochlorous acid by lipoic acid |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |pmid= 1659823 |volume= 42 |issue= 11 |pages= 2244–6 |doi= 10.1016/0006-2952(91)90363-A }}</ref> 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.<ref name=Carlson08>{{cite book |last1= Carlson |first1= DA |last2= Young |first2= KL |last3= Fischer |first3= SJ |last4= Ulrich |first4= H|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|chapter= 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 |pages= 235–70}} In {{harvnb|Packer|Patel|2008}}.</ref> 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.<ref name= "Shay08"/><ref name="ReferenceC"/><ref name="Shay in Packer"/>
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.<ref>{{cite journal |pmid= 8769129 |last1= Arnér |first1= ES |doi= 10.1006/bbrc.1996.1165 |last2= Nordberg |first2= J |last3= Holmgren |first3= A |title= Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase |journal= [[Biochemical and Biophysical Research Communications]] |volume= 225 |issue= 1 |date= August 1996 |pages= 268–74}}</ref><ref>{{cite journal |doi= 10.1667/0033-7587(2003)159[0484:RROCDA]2.0.CO;2 |pmid= 12643793 |last1= Biaglow |first1= JE |last2= Ayene |first2= IS |last3= Koch |first3= CJ |last4= Donahue |first4= J |last5= Stamato |first5= TD |last6= Mieyal |first6= JJ |last7= Tuttle |first7= SW |display-authors= 4 |title= Radiation response of cells during altered protein thiol redox |journal= Radiation Research |volume= 159 |issue= 4 |date= April 2003 |pages= 484–94 |bibcode= 2003RadR..159..484B |s2cid= 42110797 }}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(96)00400-5 |pmid= 8981046 |last1= Haramaki |first1= N |last2= Han |first2= D |last3= Handelman |first3= GJ |last4= Tritschler |first4= HJ |last5= Packer |first5= L |display-authors= 4 |title= Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid |journal= [[Free Radical Biology and Medicine]] |volume= 22 |issue= 3 |year= 1997 |pages= 535–42}}</ref><ref>{{cite journal |doi= 10.1016/0006-2952(95)00084-D |pmid= 7632170 |last1= Constantinescu |first1= A |last2= Pick |first2= U |last3= Handelman |first3= GJ |last4= Haramaki |first4= N |last5= Han |first5= D |last6= Podda |first6= M |last7= Tritschler |first7= HJ |last8= Packer |first8= L |display-authors= 4 |title= Reduction and transport of lipoic acid by human erythrocytes |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |volume= 50 |issue= 2 |date= July 1995 |pages= 253–61}}</ref><ref>{{cite journal |pmid= 16650819 |last1= May |first1= JM |doi= 10.1016/j.bbrc.2006.04.065 |last2= Qu |first2= ZC |last3= Nelson |first3= DJ |title= Cellular disulfide-reducing capacity: An integrated measure of cell redox capacity |journal= [[Biochemical and Biophysical Research Communications]] |volume= 344 |issue= 4 |date= June 2006 |pages= 1352–9}}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(02)00862-6 |pmid= 12086686 |last1= Jones |first1= W |last2= Li |first2= X |last3= Qu |first3= ZC |last4= Perriott |first4= L |last5= Whitesell |first5= RR |last6= May |first6= JM |display-authors= 4 |title= Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells |journal= [[Free Radical Biology and Medicine]] |volume= 33 |issue= 1 |date= July 2002 |pages= 83–93}}</ref><ref>{{cite journal |last1= Schempp |first1= H |last2= Ulrich |first2= H |last3= Elstner |first3= EF |title= Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase |journal= [[Zeitschrift für Naturforschung C]] |volume= 49 |issue= 9–10 |pages= 691–2 |year= 1994 |pmid= 7945680 |doi= 10.1515/znc-1994-9-1023 |doi-access= free }}</ref> Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, [[thiol-disulfide exchange reactions]].<ref>{{cite book |last1= Biewenga |first1= GP |last2= Haenen |first2= GRMM |last3= Bast |first3= A |chapter= Ch. 1: An Overview of Lipoate Chemistry |editor1-last= Fuchs |editor1-first= J |editor2-last= Packer |editor2-first= L |editor3-last= Zimmer |editor3-first= G |title= Lipoic Acid In Health & Disease |publisher= [[CRC Press]] |year= 1997 |pages= [https://books.google.com/books?id=ksWdMbxa5FkC&pg=PA1 1–32] |isbn= 9780824700935}}</ref>
RLA may function ''in vivo'' like a B-vitamin and at higher doses like plant-derived nutrients, such as [[curcumin]], [[sulforaphane]], [[resveratrol]], and other nutritional substances that induce [[Drug metabolism#Phase II – conjugation|phase II detoxification enzymes]], thus acting as cytoprotective agents.<ref name="Shay in Packer">{{cite book |last1= Shay |first1= KP |last2= Shenvi |first2= S |last3= Hagen |first3= TM |chapter= Ch. 14 Lipoic Acid as an Inducer of Phase II Detoxification Enzymes Through Activation of Nr-f2 Dependent Gene Expression|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|pages= 349–71}} In {{harvnb|Packer|Patel|2008}}.</ref><ref>{{cite journal |last1=Lii |first1= CK |last2= Liu |first2= KL |last3= Cheng |first3= YP |last4= Lin |first4= AH |last5= Chen |first5= HW |last6= Tsai |first6= CW |display-authors= 4 |title= Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation |journal= [[Journal of Nutrition]] |volume= 140 |issue= 5 |pages= 885–92 |date= May 2010 |pmid= 20237067 |doi= 10.3945/jn.110.121418 |doi-access= free }}</ref> This stress response indirectly improves the antioxidant capacity of the cell.<ref name= "Shay08">{{cite journal |pmid= 18409172 |last1= Shay |first1= KP |doi= 10.1002/iub.40 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Hagen |first4= TM |title= 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 |journal= IUBMB Life |volume= 60 |issue= 6 |date= June 2008 |pages= 362–7 |s2cid= 33008376 |doi-access= free }}</ref>
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