Tioktat kislota: Versiyalar orasidagi farq

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„Lipoic acid“ sahifasi tarjima qilib yaratildi
(Farq yoʻq)

15-Iyun 2022, 11:26 dagi koʻrinishi

Bu maqola linolenic acid haqidadir. linoleic acid —  bilan adashtirmang.

 

Tioktat kislota
Names
IUPAC nomi
(R)-5-(1,2-Dithiolan-3-yl)pentanoic acid
Boshqa nomlari
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
PubChem <abbr title="<nowiki>Compound ID</nowiki>">CID
UNII
CompTox Dashboard (<abbr title="<nowiki>U.S. Environmental Protection Agency</nowiki>">EPA)
  • 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
Xususiyatlari
C8H14O2S2
Molar massasi 206.32 g·mol−1
ko'rinishi Sariq ignaga o'xshash kristallar
Suyuqlansh harorati 60–62 °C (140–144 °F; 333–335 K)
Juda oz eriydi (0.24 g/L)[1]
Etanolda ruvchanligi (50 mg/mL) Eriydi
Farmakalogiyasi
A16AX01 (WHO)
Pharmacokinetics:
Biofoydaliligi
 30% (oral)[2]
Tegishli birikmalar
Tegishli birikmalar
 Lipoamide

Asparagusic kislota
Agar boshqacha ko'rsatilmagan bo'lsa, ma'lumotlar standart holatidagi materiallar uchun berilgan (25 °C [77 °F], 100 kPa).
☒N verify  checkY☒N

Tioktat kislota - a-lipoik kislota, alfa-lipoik kislota ( ALA ) va tioktik kislota sifatida ham tanilgan, kapril kislotasidan (oktanoik kislota) olingan organosulfur birikmasidir . [3] ALA odatda hayvonlarda ishlab chiqariladi va aerob metabolizm uchun zarurdir. Shuningdek, u antioksidant sifatida sotiladigan, ba'zi mamlakatlarda farmatsevtik dori sifatida mavjud. [3]

Fizikaviy va kimyoviy xossalari

Lipoik kislota (LA), shuningdek, a-lipoik kislota, [3] [4] alfa-lipoik kislota (ALA) va tioktik kislota [5] deb nomlanuvchi oktan kislotasidan olingan organosulfur birikmasidir . [3] LA ikki oltingugurt atomini o'z ichiga oladi (C6 va C8 da) disulfid bog'i bilan bog'langan va shuning uchun oksidlangan deb hisoblanadi, ammo oltingugurt atomlarining ikkalasi ham yuqori oksidlanish darajasida mavjud bo'lishi mumkin. [3]

C6 dagi uglerod atomi assimmetrikdir va molekula ikkita enantiomer ( R ) - (+) - lipoik kislota (RLA) va ( S ) - (-) - lipoik kislota (SLA) va rasemik aralashma ( R / S ) shaklida mavjud. )-lipoik kislota (R/S-LA).

LA fizik jihatdan sariq rangli qattiq modda sifatida ko'rinadi va tizimli ravishda terminal karboksilik kislota va terminal ditiolan halqasini o'z ichiga oladi.

Oziq- ovqat qo'shimchalari materiallari va dorixonalarda foydalanish uchun USP R / S-LA uchun rasmiy monografiya yaratdi. [6] [7]

Biologik funktsiya

"Lipoat" lipoik kislotaning konjugat asosidir va fiziologik sharoitda LA ning eng keng tarqalgan shakli. [3] Ko'pgina endogen ishlab chiqarilgan RLA "erkin" emas, chunki RLA ning prekursori bo'lgan oktan kislotasi oltingugurt atomlarining fermentativ kiritilishidan oldin ferment komplekslari bilan bog'langan. Kofaktor sifatida RLA fermentning lipoil domenlarining terminal lizin qoldig'iga amid bog'i orqali kovalent bog'langan. RLA ning eng ko'p o'rganilgan rollaridan biri piruvat dehidrogenaza kompleksining (PDC yoki PDHC) kofaktori bo'lib, u boshqa fermentativ tizimlarda ham kofaktordir (quyida tavsiflangan). [3]

Tabiatda faqat ( R ) - (+) - enantiomer (RLA) mavjud va aerob metabolizm uchun zarurdir, chunki RLA ko'plab ferment komplekslarining muhim kofaktoridir . [3]

Biosintez va birikmalar

Lipoik kislotaning prekursori, oktan kislotasi, oktanoil- atsil tashuvchi oqsil shaklida yog 'kislotasi biosintezi orqali amalga oshiriladi. [3] Eukariotlarda bu maqsadda mitoxondriyadagi ikkinchi yog 'kislotalarining biosintetik yo'li ishlatiladi. [3] Oktanoat oktanoiltransferaza deb ataladigan ferment tomonidan yog 'kislotasi biosintezidan lipoil domeni oqsilining amidiga asil tashuvchi oqsilning tioesteri sifatida o'tkaziladi. [3] Oktanoatning ikkita vodorodi lipoil sintaza tomonidan radikal SAM mexanizmi orqali oltingugurt guruhlari bilan almashtiriladi. [3] Natijada, oqsillarga biriktirilgan lipoik kislota sintezlanadi va erkin lipoik kislota hosil bo'lmaydi. Lipoik kislota oqsillar parchalanganda va lipoamidaza fermenti ta'sirida olib tashlanishi mumkin. [8] Erkin lipoat ba'zi organizmlar tomonidan lipoat protein ligaza deb ataladigan ferment sifatida ishlatilishi mumkin va uni to'g'ri oqsilga kovalent tarzda biriktiradi. Ushbu fermentning ligaza faolligi ATP ni talab qiladi. [9]

Hujayraviy transport

Natriy va biotin (B7) va pantotenik kislota (B5) vitaminlari bilan bir qatorda lipoik kislota hujayralarga SMVT (natriyga bog'liq multivitamin tashuvchisi) orqali kiradi. SMVT tomonidan tashiladigan birikmalarning har biri boshqalar bilan raqobatbardoshdir. Masalan, tadqiqotlar shuni ko'rsatdiki, lipoik kislota [10] yoki pantotenik kislota [11] ni ko'paytirish biotinning so'rilishini va/yoki biotinga bog'liq fermentlar faoliyatini kamaytiradi.

Enzimatik faollik

Lipoik kislota kamida beshta ferment tizimining kofaktoridir . [3] Ulardan ikkitasi limon kislotasi aylanishida bo'lib, ko'plab organizmlar ozuqa moddalarini energiyaga aylantiradi. Lipoillangan fermentlar ularga kovalent tarzda biriktirilgan lipoik kislotaga ega. Lipoil guruhi 2-oksoatsid dehidrogenaza komplekslarida asil guruhlarini va glitsin parchalanish kompleksida yoki glitsin dehidrogenazada metilamin guruhini o'tkazadi. [3]

2-oksoatsid dehidrogenaza o'tkazish reaktsiyalari shunga o'xshash mexanizm bilan sodir bo'ladi:

  • piruvat dehidrogenaza kompleksi
  • a-ketoglutarat dehidrogenaza yoki 2-oksoglutarat dehidrogenaza kompleksi
  • Tarmoqlangan zanjirli oksoatsid dehidrogenaza (BCDH) kompleksi
  • atsetoin dehidrogenaza kompleksi.

Ulardan eng ko'p o'rganilgani piruvat dehidrogenaza kompleksidir. [3] Ushbu komplekslar uchta markaziy bo'linmaga ega: E1-3, mos ravishda dekarboksilaza, lipoil transferaza va digidrolipoamid degidrogenaza . Ushbu komplekslar markaziy E2 yadrosiga ega va boshqa subbirliklar kompleksni hosil qilish uchun bu yadroni o'rab oladi. Ushbu ikki bo'linma orasidagi bo'shliqda lipoil domeni faol saytlar orasidagi oraliqlarni olib boradi. [3] Lipoil domenining o'zi E2 yadrosiga moslashuvchan bog'lovchi tomonidan biriktirilgan va lipoil domenlari soni ma'lum bir organizm uchun birdan uchgacha o'zgaradi. Domenlar soni eksperimental ravishda o'zgartirildi va to'qqizdan ortiq qo'shilmaguncha o'sishga unchalik ta'sir ko'rsatmaydi, garchi kompleksning faolligi uchdan ko'proq kamaydi. [12]

Lipoik kislota atsetoin (3-gidroksi-2-butanon) ning asetaldegid va atsetil koenzim A ga aylanishini katalizlovchi atsetoin dehidrogenaza kompleksining ko-faktori bo'lib xizmat qiladi. [3]

Glitsin ajralish tizimi boshqa komplekslardan farq qiladi va boshqa nomenklaturaga ega. [3] Ushbu tizimda H oqsili qo'shimcha spirallarga ega bo'lgan erkin lipoil domenidir, L oqsili digidrolipoamid degidrogenaza, P oqsili dekarboksilaza va T oqsili metilaminni lipoatdan tetrahidrofolatga (THF) o'tkazib, metilen-THF va ammiak. Metilen-THF keyinchalik serin gidroksimetiltransferaza tomonidan serinni glitsindan sintez qilish uchun ishlatiladi. Ushbu tizim o'simliklarning fotosintez olish qismidir. [13]

Biologik manbalar va degradatsiya

Lipoik kislota oqsillardagi lizin bilan bog'langan ko'plab oziq-ovqatlarda mavjud [3], ammo buyraklar, yurak, jigar, ismaloq, brokkoli va xamirturush ekstraktida bir oz ko'proq. [14] Tabiiy ravishda paydo bo'lgan lipoik kislota har doim kovalent bog'langan va oziq-ovqat manbalaridan osongina mavjud emas. [3] Bundan tashqari, oziq-ovqat manbalarida mavjud bo'lgan lipoik kislota miqdori past. Masalan, lipoik kislotani tozalashda uning tuzilishini aniqlash uchun taxminan 10 tonna jigar qoldig'i ishlatilgan, bundan esa 30  mg lipoik kislota hosil bo'lgan.. [15] Natijada, qo'shimcha sifatida mavjud bo'lgan barcha lipoik kislota kimyoviy sintezlanadi.

RLA va R-DHLA ning boshlang'ich darajalari (qo'shimchalar kiritishdan oldin) inson plazmasida aniqlanmagan. [16] Protein bilan bog'langan lipoik kislotani chiqaradigan kislota gidrolizidan keyin RLA 12.3−43.1 ng/mL aniqlandi  . Protein bilan bog'langan lipoik kislotaning fermentativ gidrolizi 1,4-11,6 ng/ml ni va <1-38,2 ng/mL mos ravishda subtilisin va alkalaz yordamida chiqaradi  . [17] [18] [19]

Ovqat hazm qilish proteolitik fermentlari oziq-ovqatdan olingan mitoxondrial ferment komplekslaridan R-lipoillizin qoldig'ini ajratadi, lekin lipoik kislota - L - lizin amid bog'ini ajrata olmaydi. [20] Sintetik lipoamid ham, ( R )-lipoil- L -lizin ham sarum lipoamidazalari tomonidan tez parchalanadi, ular erkin ( R )-lipoik kislota va L -lizin yoki ammiakni chiqaradi. [3] Sisteindan tashqari, lipoik kislota kabi alifatik sulfidlarning degradatsiyasi va ulardan foydalanish haqida kam narsa ma'lum. [3]

Lipoik kislota sutemizuvchilarga oziq-ovqat qo'shimchasi sifatida berilganda turli yo'llar bilan metabollanadi. [3] [21] Tetranorlipoik kislotaga parchalanishi, oltingugurt atomlarining bir yoki ikkalasining sulfoksidga oksidlanishi va sulfidning S-metilatsiyasi kuzatildi. O'zgartirilmagan lipoik kislotaning glitsinga konjugasiyasi ayniqsa sichqonlarda aniqlangan. [21] Lipoik kislotaning parchalanishi odamlarda shunga o'xshash, ammo oltingugurt atomlarining sezilarli darajada oksidlanishi aniq emas. [3] [22] Ko'rinib turibdiki, sutemizuvchilar lipoik kislotadan oltingugurt manbai sifatida foydalanishga qodir emaslar.

Kimyoviy sintezi

( R )-Lipoik kislota (RLA, yuqori) va ( S )-lipoik kislota (SLA, pastda). ( R ) - va ( S ) - lipoik kislotaning 1: 1 aralashmasi ( rasemat ) ( RS ) - lipoik kislota yoki (±) - lipoik kislota (R/S-LA) deb ataladi.

1952 yilda kimyoviy sintezdan oldin SLA mavjud emas edi [23] [24] Ishlab chiqarish jarayonida SLA RLA bilan teng miqdorda ishlab chiqariladi. Rasemik shakl LA ning turli shakllari bioekvivalent emasligi erta tan olinganiga qaramay, 1950-1960 yillarda Evropa va Yaponiyada klinik jihatdan kengroq qo'llanilgan. [25] RLA va SLA uchun birinchi sintetik protseduralar 1950-yillarning o'rtalarida paydo bo'lgan. [26] [27] [28] [29] Xiral kimyodagi yutuqlar klassik rezolyutsiya va assimetrik sintez orqali yagona enantiomerlarni ishlab chiqarish uchun yanada samarali texnologiyalarga olib keldi va bu vaqtda RLA ga talab ham o'sdi. 21-asrda yuqori kimyoviy va/yoki optik tozalikka ega R/S-LA, RLA va SLA sanoat miqdorida mavjud. Hozirgi vaqtda R/S-LA va RLA jahon yetkazib berishning katta qismi Xitoyda, kamroq miqdorda esa Italiya, Germaniya va Yaponiyada ishlab chiqariladi. RLA birinchi marta doktorlik dissertatsiyasida Georg Lang tomonidan tasvirlangan jarayonning modifikatsiyalari orqali ishlab chiqariladi. dissertatsiya va keyinchalik DeGussa tomonidan patentlangan. RLA metabolizmdagi "vitaminga o'xshash" roli tufayli ozuqaviy jihatdan ma'qullangan bo'lsa-da, RLA va R/S-LA dieta qo'shimchalari sifatida keng tarqalgan. Stereospesifik va stereospesifik bo'lmagan reaktsiyalar in vivo jonli ravishda sodir bo'lishi va ta'sir mexanizmlariga hissa qo'shishi ma'lum, ammo hozirgi kunga qadar dalillar RLA eutomer bo'lishi mumkinligini ko'rsatadi (ozuqaviy va terapevtik jihatdan afzal qilingan shakl). [30] [31]

Farmakologiya

Farmakokinetika

2007 yilda natriy RLA ning inson farmakokinetik tadqiqotlari shuni ko'rsatdiki, plazmadagi maksimal kontsentratsiya va biofoydalilik erkin kislota shakliga qaraganda sezilarli darajada yuqori va erkin kislota shaklini tomir ichiga yuborish orqali erishilgan plazma kontsentratsiyasi bilan raqobatlashadi. [32] Bundan tashqari, Nrf2 faollashtirilgan hayvonlar modellari bilan taqqoslanadigan yuqori plazma darajalariga erishildi. [32]

LA ning turli shakllari bioekvivalent emas. Juda kam tadqiqotlar individual enantiomerlarni rasemik lipoik kislota bilan solishtirishadi. Ikki barobar ko'p rasemik lipoik kislota RLA o'rnini bosa oladimi yoki yo'qmi, aniq emas. [32]

Mushuklarda LA ning toksik dozasi odamlar yoki itlarga qaraganda ancha past bo'lib, gepatotsellyulyar toksiklikni keltirib chiqaradi. [33]

Farmakodinamikasi

Organizmga tashqaridan yuborilganda lipoik kislotaning mexanizmi va ta'siri bahsli. Hujayradagi lipoik kislota erkin radikallarni to'g'ridan-to'g'ri tozalashdan ko'ra, birinchi navbatda oksidlovchi stress reaktsiyasini keltirib chiqaradi. Bu ta'sir RLA uchun xosdir. [4] Kuchli kamaytiruvchi muhitga qaramay, LA hujayra ichidagi oksidlangan va qaytarilgan shakllarda aniqlangan. [34] LA uzoq inkubatsiya vaqtlari tufayli biokimyoviy tahlilda reaktiv kislorod va reaktiv azot turlarini tozalashga qodir, ammo bu hujayra ichida sodir bo'lishi yoki radikal tozalash LA ta'sirining asosiy mexanizmlariga hissa qo'shishi haqida juda kam dalil mavjud. [4] [35] LA ning gipoxloroz kislotaga nisbatan yaxshi tozalash faolligi (neytrofillar tomonidan ishlab chiqariladigan yallig'lanish va to'qimalarning shikastlanishiga olib kelishi mumkin bo'lgan bakteritsid) DHLA ni kamaytirishda yo'qolgan 5 a'zoli ditiolin halqasining kuchlanishli konformatsiyasi bilan bog'liq. Hujayralarda LA digidrolipoik kislotaga kamayadi, bu odatda LA ning ko'proq biofaol shakli hisoblanadi va antioksidant ta'sirlarning ko'pchiligi va bog'lanmagan temir va misning oksidlanish-qaytarilish faolligini pasaytirish uchun javobgardir. [36] Bu nazariya ikkita erkin sulfgidrilning yuqori reaktivligi, DHLA ning past hujayra ichidagi konsentratsiyasi, shuningdek, bir yoki ikkala sulfgidrilning tez metillanishi, qisqaroq metabolitlarga tez yon zanjir oksidlanishi va hujayradan tez oqib chiqishi tufayli e'tiroz bildirildi. DHLA ham, LA ham kiritilgandan so'ng hujayralar ichida topilgan bo'lsa-da, ko'pchilik hujayra ichidagi DHLA sitozolik va mitoxondriyal oqsillarning turli sistein qoldiqlari bilan aralash disulfidlar shaklida mavjud. [30] So'nggi topilmalar shuni ko'rsatadiki, terapevtik va qarishga qarshi ta'sir hujayraning antioksidant holatini yaxshilaydigan signal uzatish va gen transkripsiyasining modulyatsiyasi bilan bog'liq. Biroq, bu radikal tozalash yoki kamaytirish ta'siri bilan emas, balki prooksidant mexanizmlar orqali sodir bo'ladi. [4] [35] [37]

LA ning barcha disulfid shakllari (R/S-LA, RLA va SLA) DHLA ga kamaytirilishi mumkin, ammo model tizimlarida ham to'qimalarga xos, ham stereoselektiv (bir enantiomerni boshqasidan afzal ko'rish) pasayishlar qayd etilgan. Kamida ikkita sitozolik ferment, glutation reduktaza (GR) va tioredoksin reduktaza (Trx1) va ikkita mitoxondrial ferment, lipoamid dehidrogenaza va tioredoksin reduktaza (Trx2) LA ni kamaytiradi. SLA sitozolik GR tomonidan stereoselektiv ravishda kamayadi, Trx1, Trx2 va lipoamid dehidrogenaza stereoselektiv ravishda RLA ni kamaytiradi. ( R )-(+)-lipoik kislota enzimatik yoki kimyoviy yoʻl bilan ( R )-(-)-dihidrolipoy kislotaga, ( S )-(-)-lipoik kislota esa ( S )-(+)-dihidrolipoy kislotaga qaytariladi. . [38] [39] [40] [41] [42] [43] [44] Dihidrolipoy kislotasi (DHLA) fermentativ bo'lmagan, tiol-disulfid almashinuvi reaktsiyalari orqali hujayra ichida va hujayradan tashqarida ham hosil bo'lishi mumkin. [45]

RLA in vivo jonli ravishda B vitamini kabi va o'simlikdan olingan ozuqa moddalari, masalan, kurkumin, sulforafan, resveratrol va II fazani detoksifikatsiya qiluvchi fermentlarni qo'zg'atuvchi boshqa ozuqaviy moddalar kabi yuqori dozalarda ishlaydi va shu bilan sitoprotektiv vositalar sifatida ishlaydi. [37] [46] Ushbu stress reaktsiyasi bilvosita hujayraning antioksidant qobiliyatini yaxshilaydi. [4]

LA ning ( S )-enantiomeri tiamin yetishmaydigan kalamushlarga qo‘llanganda zaharli ekanligi ko‘rsatilgan. [47] [48]

Bir qator tadqiqotlar shuni ko'rsatdiki, SLA yoki RLA'dan pastroq faollikka ega yoki raqobatbardosh inhibisyon orqali RLA'nın o'ziga xos ta'siriga aralashadi. [49] [50] [51] [52]

Qo'llanishi

R/S-LA va RLA Qo'shma Shtatlarda kapsulalar va suvli suyuqliklar ko'rinishidagi retseptsiz oziq-ovqat qo'shimchalari sifatida keng tarqalgan va antioksidantlar sifatida sotilgan. [3]

Tana LA ni sintez qilishi mumkin bo'lsa-da, u dietadan ham so'rilishi mumkin. Gastrointestinal so'rilish o'zgaruvchan bo'lib, oziq-ovqatdan foydalanish bilan kamayadi. Shuning uchun dietali LA ni ovqatdan 30-60 daqiqa oldin yoki kamida 120 daqiqadan keyin olish tavsiya etiladi. Qondagi LA ning maksimal darajalariga dietani qo'shgandan keyin 30-60 daqiqadan so'ng erishiladi va u asosan jigarda metabollanadi deb hisoblanadi. [53]

Germaniyada LA 1966 yildan beri diabetik neyropatiyani davolash uchun dori sifatida tasdiqlangan va retseptsiz farmatsevtika sifatida mavjud. [54]

Boshqa lipoik kislotalar

  • b-lipoik kislota a-lipoik kislotaning tiosulfinati

Shuningdek qarang

  • Aminolevulin kislotasi

Manbalar

  1. ↑ "Lipoic Acid". Pubmed. NCBI. Retrieved October 18, 2018.
  2. ↑ Teichert, J; Hermann, R; Ruus, P; Preiss, R (November 2003).
  3. ↑ 3,00 3,01 3,02 3,03 3,04 3,05 3,06 3,07 3,08 3,09 3,10 3,11 3,12 3,13 3,14 3,15 3,16 3,17 3,18 3,19 3,20 3,21 3,22 3,23 3,24 „Lipoic acid“. Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis (2019-yil 1-yanvar). Qaraldi: 2019-yil 5-noyabr. Manba xatosi: Invalid <ref> tag; name "lpi" defined multiple times with different content
  4. ↑ 4,0 4,1 4,2 4,3 4,4 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.  Manba xatosi: Invalid <ref> tag; name "Shay08" defined multiple times with different content
  5. ↑ 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. 
  6. ↑ USP32-NF27 — 1042 bet. 
  7. ↑ Pharmacopeial Forum. 34. p. 1209. 
  8. ↑ 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. PMID 15528186. 
  9. ↑ Cronan, JE. Function, attachment and synthesis of lipoic acid in Escherichia coli, Advances in Microbial Physiology Poole: , 2005 — 103–46 bet. DOI:10.1016/S0065-2911(05)50003-1. ISBN 9780120277506. 
  10. ↑ Zempleni, J.; Trusty, T. A.; Mock, D. M. (1997). "Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver". The Journal of Nutrition 127 (9): 1776–81. doi:10.1093/jn/127.9.1776. PMID 9278559. 
  11. ↑ Chirapu, S. R.; Rotter, C. J.; Miller, E. L.; Varma, M. V.; Dow, R. L.; Finn, M. G. (2013). "High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid". Current Topics in Medicinal Chemistry 13 (7): 837–42. doi:10.2174/1568026611313070006. PMID 23578027. https://pubmed.ncbi.nlm.nih.gov/23578027/. 
  12. ↑ 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. 
  13. ↑ 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. 
  14. ↑ 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. 
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  16. ↑ 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. 
  17. ↑ Teichert, J. High-performance Liquid Chromatography Methods for Determination of Lipoic and Dihydrolipoic Acid in Human Plasma, Methods in Enzymology, 1997 — 159–66 bet. DOI:10.1016/S0076-6879(97)79019-0. ISBN 9780121821807. 
  18. ↑ 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. 
  19. ↑ 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. 
  20. ↑ 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. 
  21. ↑ 21,0 21,1 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. 
  22. ↑ 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. 
  23. ↑ 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. 
  24. ↑ 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. 
  25. ↑ Kleeman, A; Borbe, HO; Ulrich, H (1991). "Thioctsäure: Neue Biochemische, Pharmakologische und Klinische Erkenntnisse zur Thioctsäure". in Borbe, HO; Ulrich, H. [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. 
  26. ↑ Fontanella, L (1955). "Preparation of optical antipodes of alpha-lipoic acid". Il Farmaco; Edizione Scientifica 10 (12): 1043–5. PMID 13294188. 
  27. ↑ 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. doi:10.1021/ja01624a057. 
  28. ↑ 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. 
  29. ↑ Deguchi, Y; Miura, K (June 1964). "Studies on the synthesis of thioctic acid and its related compounds. XIV. Synthesis of (+)-thioctamide". Yakugaku Zasshi 84 (6): 562–3. doi:10.1248/yakushi1947.84.6_562. PMID 14207116. 
  30. ↑ 30,0 30,1 Carlson, DA „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 — 235–70 bet.  Manba xatosi: Invalid <ref> tag; name "Carlson08" defined multiple times with different content
  31. ↑ Packer, L; Kraemer, K; Rimbach, G (October 2001). "Molecular aspects of lipoic acid in the prevention of diabetes complications". Nutrition 17 (10): 888–95. doi:10.1016/S0899-9007(01)00658-X. PMID 11684397. 
  32. ↑ 32,0 32,1 32,2 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". Alternative Medicine Review 12 (4): 343–51. PMID 18069903. http://www.altmedrev.com/publications/12/4/343.pdf.  Manba xatosi: Invalid <ref> tag; name "ReferenceB" defined multiple times with different content
  33. ↑ 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. 
  34. ↑ 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. 
  35. ↑ 35,0 35,1 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 (BBA) - General Subjects 1790 (10): 1149–60. doi:10.1016/j.bbagen.2009.07.026. PMID 19664690. PMC 2756298. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2756298. 
  36. ↑ 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. 
  37. ↑ 37,0 37,1 Shay, KP „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 — 349–71 bet.  Manba xatosi: Invalid <ref> tag; name "Shay in Packer" defined multiple times with different content
  38. ↑ 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. 
  39. ↑ 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. 
  40. ↑ 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. 
  41. ↑ Constantinescu, A; Pick, U; Handelman, GJ; Haramaki, N et al. (July 1995). "Reduction and transport of lipoic acid by human erythrocytes". Biochemical Pharmacology 50 (2): 253–61. doi:10.1016/0006-2952(95)00084-D. PMID 7632170. 
  42. ↑ May, JM; Qu, ZC; Nelson, DJ (June 2006). "Cellular disulfide-reducing capacity: An integrated measure of cell redox capacity". Biochemical and Biophysical Research Communications 344 (4): 1352–9. doi:10.1016/j.bbrc.2006.04.065. PMID 16650819. 
  43. ↑ Jones, W; Li, X; Qu, ZC; Perriott, L et al. (July 2002). "Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells". Free Radical Biology and Medicine 33 (1): 83–93. doi:10.1016/S0891-5849(02)00862-6. PMID 12086686. 
  44. ↑ Schempp, H; Ulrich, H; Elstner, EF (1994). "Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase". Zeitschrift für Naturforschung C 49 (9–10): 691–2. doi:10.1515/znc-1994-9-1023. PMID 7945680. 
  45. ↑ Biewenga, GP „Ch. 1: An Overview of Lipoate Chemistry“,. Lipoic Acid In Health & Disease Fuchs: . CRC Press, 1997 — 1–32 bet. ISBN 9780824700935. 
  46. ↑ Lii, CK; Liu, KL; Cheng, YP; Lin, AH et al. (May 2010). "Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation". Journal of Nutrition 140 (5): 885–92. doi:10.3945/jn.110.121418. PMID 20237067. 
  47. ↑ Gal, EM; Razevska, DE (August 1960). "Studies on the in vivo metabolism of lipoic acid. 1. The fate of DL-lipoic acid-S35 in normal and thiamine-deficient rats". Archives of Biochemistry and Biophysics 89 (2): 253–61. doi:10.1016/0003-9861(60)90051-5. PMID 13825981. 
  48. ↑ Gal, EM (July 1965). "Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats". Nature 207 (996): 535. doi:10.1038/207535a0. PMID 5328673. 
  49. ↑ Kilic, F; Handelman, GJ; Serbinova, E; Packer, L et al. (October 1995). "Modelling cortical cataractogenesis 17: In vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis". Biochemistry and Molecular Biology International 37 (2): 361–70. PMID 8673020. 
  50. ↑ Artwohl, M; Schmetterer, L; Rainer, G et al. (September 2000). "Modulation by antioxidants of endothelial apoptosis, proliferation, & associated gene/protein expression". 43. 36th Annual Meeting of the European Association for the Study of Diabetes, 17–21 September 2000, Jerusalem, Israel. (published August 2000). Abs 274. PMID 11008622. 
  51. ↑ Streeper, RS; Henriksen, EJ; Jacob, S; Hokama, JY et al. (July 1997). "Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle". AJP: Endocrinology and Metabolism 273 (1 Pt 1): E185–91. doi:10.1152/ajpendo.1997.273.1.E185. PMID 9252495. 
  52. ↑ Frölich, L; Götz, ME; Weinmüller, M; Youdim, MB et al. (March 2004). "(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia". Journal of Neural Transmission 111 (3): 295–310. doi:10.1007/s00702-003-0043-5. PMID 14991456. 
  53. ↑ McIlduff, Courtney E; Rutkove, Seward B (2011-01-01). "Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy". Therapeutics and Clinical Risk Management 7: 377–385. doi:10.2147/TCRM.S11325. ISSN 1176-6336. PMID 21941444. PMC 3176171. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3176171. 
  54. ↑ Ziegle, D.; Reljanovic, M; Mehnert, H; Gries, F. A. (1999). "α-Lipoic acid in the treatment of diabetic polyneuropathy in Germany". Experimental and Clinical Endocrinology & Diabetes 107 (7): 421–30. doi:10.1055/s-0029-1212132. PMID 10595592. 

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