PHYSIOLOGICAL ROLE OF GLUTATHIONE IN THE HUMAN BODY (LECTURE)
Abstract
Glutathione tripeptide is a small thiol molecule, which protects the body from reactive oxygen forms, aging, exposure to xenobiotics, destructive inflammation, various forms of cell death, and many diseases that are the leading causes of mortality worldwide. Glutathione is found in all animal cells. It ensures optimal performance under the effect of various adverse environmental factors. The report gives an overview of the structure and synthesis of glutathione in the body, its key role in the formation of antioxidant protection, detoxification of exogenous and endogenous xenobiotics. We discuss the participation of the glutathione system in the innate and acquired immune response processes, programmed cell death, cell proliferation, DNA repair and synthesis. The article provides a list of factors that cause glutathione system depletion followed by a decrease in the reserve capacity of the cell, up to its death. The content of glutathione in food products and the possibility of its transport into the internal environment from food are discussed. Changes in the content of glutathione depending on the methods of its introduction into the body are considered. The objective was to provide the variety of physiological aspects of the role of glutathione, to give a complex impression of the importance of this molecule for the body, to demonstrate the significance and possibility of preventing depletion of the glutathione system.
References
Алексеев В.В., Алипов А.Н., Андреев В.А. и др. Медицинские лабораторные технологии. Том 2. М.: ГЭОТАР-Медиа; 2013.
Баранов И., Гладин Д., Козлова Н. Взаимосвязь гиперактивации сигнального пути mTOR, процессов старения и патогенеза COVID-19 (обзор литературы). Russian Biomedical Research (Российские биомедицинские исследования). 2023;8(2):64–77. DOI: 10.56871/RBR.2023.18.67.009.
Борисенок О.А., Бушма М.И., Басалай О.Н., Радковец А.Ю. Биологическая роль глутатиона. Медицинские новости. 2019;7(298):3–8.
Кулинский В.И., Колесниченко Л.С. Система глутатиона. I. Синтез, транспорт, глутатионтрансферазы, глутатионпероксидазы. Биомедицинская химия. 2009;55(3):255–277.
Переверзев А.П., Романовский Р.Р., Шаталова Н.А. Остроумова О.Д. Инфламэйджинг: воспаление и оксидативный стресс как причина старения и развития когнитивных нарушений. Медицинский совет. 2021;(4):48–58.
Пилат Т.Л. Биологически активные вещества продуктов питания и их влияние на процесс детоксикации ксенобиотиков. В кн.: Пилат Т.Л., Кузьмина Л.П., Измерова Н.И. Детоксикационное питание. М.: ГЭОТАР-Медиа; 2012:112–143.
Толпыгина О.А. Роль глутатиона в системе антиоксидантной защиты (Обзор). Бюллетень ВСНЦ СО РАМН. 2012;2(84,Ч.2):178–180.
Хайцев Н.В., Васильев А.Г., Трашков А.П., Кравцова А.А., Балашов Л.Д. Влияние возраста и пола на характер ответных реакций белых крыс при действии хронической гипоксической гипоксии. Педиатр. 2015;6(2):71–77. DOI: 10.17816/PED6271-77.
Allen J., Bradley R.D. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J. Altern. Complement. Med. 2011;17:827–833.
Anderson M.E., Underwood M., Bridges R.J., Meister A. Glutathione metabolism at the blood-cerebrospinal fluid barrier. FASEB J. 1989;3(13):2527–31. DOI: 10.1096/fasebj.3.13.2572501.
Asemi Z., Samimi M., Tabassi Z., Shakeri H., Sabihi S.S., Esmaillzadeh A. Effects of DASH diet on lipid profiles and biomarkers of oxidative stress in overweight and obese women with polycystic ovary syndrome: A randomized clinical trial. Nutrition. 2014;30:1287–1293.
Asemi Z., Samimi M., Tabassi Z., Sabihi S.S., Esmaillzadeh A. A randomized controlled clinical trial investigating the effect of DASH diet on insulin resistance, inflammation, and oxidative stress in gestational diabetes. Nutrition. 2013;29:619–624.
Averill-Bates D. The antioxidant glutathione. Vitam Horm. 2023;121:109–141.
Bajic V.P., Van Neste C., Obradovic M., Zafirovic S., Radak D., Bajic V.B., Essack M., Isenovic E.R. Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease. Oxid Med Cell Longev. 2019;2019:5028181. DOI: 10.1155/2019/5028181.
Ballatori N., Krance S.M., Marchan R., Hammond C.L. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med. 2009;30(1-2):13–28.
Ballatori N., Truong A.T., Ma A.K., Boyer J.L. Determinants of glutathione efflux and biliary GSH/GSSG ratio in perfused rat liver. Am J Physiol. 1989;256:482–490.
Bennani-Baiti B., Toegel S., Viernstein H., Urban E., Noe C.R., Bennani-Baiti I. MInflammation modulates RLIP76/RALBP1 electrophile-glutathione conjugate transporter and housekeeping genes in human blood–brain barrier endothelial cells. PLoS One. 2015;10(9):e0139101.
Bettermann E.L., Hartman T.J., Easley K.A., Ferranti E.P., Jones D.P., Quyyumi A.A., Vaccarino V., Ziegler T.R., Alvarez J.A. Higher Mediterranean Diet Quality Scores and Lower Body Mass Index Are Associated with a Less-Oxidized Plasma Glutathione and Cysteine Redox Status in Adults. J. Nutr. 2018;148:245–253.
Biolo G., Antonione R., De M. Glutathione metabolism in sepsis. Review Crit Care Med. 2007;35(9 Suppl):S591–5.
Bjørklund G., Peana M., Maes M., Dadar M., Severin B. The glutathione system in Parkinson's disease and its progression. Neurosci Biobehav Rev. 2021;120:470–478.
Bjørklund G., Tinkov A.A., Hosnedlová B., Kizek R., Ajsuvakova O.P., Chirumbolo S., Skalnaya M.G., Peana M., Dadar M., El-Ansary A., Qasem H., Adams J.B., Aaseth J., Skalny A.V. The role of glutathione redox imbalance in autism spectrum disorder: A review. Free Radic Biol Med. 2020;160:149–162. DOI: 10.1016/j.freeradbiomed.2020.07.017.
Campolo J., Bernardi S., Cozzi L., Rocchiccioli S., Dellanoce C., Cecchettini A., Tonini A., Parolini M., De Chiara B., Micheloni G. et al. Medium-term effect of sublingual l-glutathione supplementation on flow-mediated dilation in subjects with cardiovascular risk factors. Nutrition. 2017;38:41–47.
Cao J.Y., Dixon S. J Mechanisms of ferroptosis. Cell. Mol. Life Sci., 2016;73:2195–2209.
Connor M.J., Wheeler L.A. Depletion of cutaneous glutathione by ultraviolet radiation. Photochem Photobiol. 1987;46(2):239–45.
Conrad M., Kagan V.E., Bayir H., Pagnussat G.C., Head B. et. al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 2018;32:602–619.
Dai J., Jones D.P., Goldberg J., Ziegler T.R., Bostick R.M., Wilson P.W., Manatunga A.K., Shallenberger L., Jones L., Vaccarino V. Association between adherence to the Mediterranean diet and oxidative stress. Am J Clin Nutr. 2008;88:1364–1370.
Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev EM. et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic. Cell Death. Cell. 2012;149:1060–1072.
Franco R., Panayiotidis M.I., Cidlowski J.A. Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation. J Biol Chem. 2007;282(42):30452–30465. DOI: 10.1074/jbc.M703091200.
Furukawa T., Meydani S.N., Blumberg J.B. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech. Ageing Dev. 1987;38:107–117.
García-Giménez J.L., Markovic J., Dasí F., Queval G., Schnaubelt D., Foyer C.H. et al. Nuclear glutathione. Biochim Biophys Acta. 2013;1830:3304–16. 10.1016/j.bbagen.2012.10.005.
Genestra M. Oxyl radicals, redox-sensitive signaling cascades and antioxidants. Cell Signal. 2007;19:1807–1819.
Gould R., Pazdro R. Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis. Nutrients. 2019;11(5):1056.
Haldar S., Rowland I.R., Barnett Y.A., Bradbury I., Robson P.J., Powell J., Fletcher J. Influence of habitual diet on antioxidant status: A study in a population of vegetarians and omnivores. Eur. J. Clin. Nutr. 2007;61:1011–1022.
Kahleova H., Matoulek M., Malinska H., Oliyarnik O., Kazdova L., Neskudla T., Skoch A., Hajek M., Hill M., Kahle M. et al. Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with Type 2 diabetes. Diabet. Med. 2011; 28:549–559.
Khan M., Yi F., Rasul A. et al. Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction. IUBMB life. 2012;64(9):783–794. DOI: 10.1002/iub.1068.
Khanfar A., Qaroot B.A. Could glutathione depletion be the Trojan horse of COVID-19 mortality? Eur Rev Med Pharmacol Sci., 2020;24(23):12500–12509.
Kim M.K., Cho S.W., Park Y.K. Long-term vegetarians have low oxidative stress, body fat, and cholesterol levels. Nutr. Res. Pract. 2012;6:155–161.
Kim S.J., Han D., Ahn B.H., Rhee J.S. Effect of glutathione, catechin, and epicatechin on the survival of Drosophila melanogaster under paraquat treatment. Biosci. Biotechnol. Biochem. 1997;61:225–229.
Krajcovicova-Kudlackova M., Simoncic R., Bederova A., Brtkova A., Magalova T., Bartekova S. Alternative nutrition and glutathione levels. Casopis Lekaru Ceskych. 1999;138:528–531.
Kumar P., Liu C., Hsu J.W., Chacko S., Minard C., Jahoor F., Sekhar R.V. Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial. Clin Transl Med. 2021;11(3):e372. DOI: 10.1002/ctm2.372.
Kuppner M.C., Scharner A., Milani V. et al. Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion. Blood. 2003;102(10):3668–3674.
Labarrere C.A., Kassab G.S. Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation. Front Nutr. 2022;9:1007816. DOI: 10.3389/fnut.2022.1007816.
Lee S., Lee J., Lee H., Sung J. J. Relative protective activities of quercetin, quercetin-3-glucoside, and rutin in alcohol-induced liver injury. Food Biochem., 2019;43(11):e13002. DOI: 10.1111/jfbc.13002.
Lei G.-S., Zhang C., Cheng B.-H., Lee C.-H. Mechanisms of Action of Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia. Antimicrob Agents Chemother. 2017;61(10).
Li L., Zhang G.F., Lee K., Lopez R., Previs S.F., Willard B., McCullough A., Kasumov T. A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis. Free Radic Biol. Med. 2016;96:13–21.
Lim J.C., Grey A.C., Zahraei A., Donaldson P.J. Age-dependent changes in glutathione metabolism pathways in the lens: New insights into therapeutic strategies to prevent cataract formation-A review. Clin Exp Ophthalmol. 2020;48(8):1031–1042. DOI: 10.1111/ceo.13801.
Meister A. Glutathione, ascorbate and cellular protection. Cancer Res. 1994;54:1969S–1975S.
Meister A. On the discovery of glutathione. Trends Biochem Sci. 1988;13(5):185–8. DOI: 10.1016/0968-0004(88)90148-x.
Minich D.M., Brown B.I. A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients. 2019;11(9):2073. DOI: 10.3390/nu11092073.
Moine L., Rivoira M., Díaz de Barboza G., Pérez A., Tolosa de Talamoni N. Glutathione depleting drugs, antioxidants and intestinal calcium absorption. World J Gastroenterol. 2018;24(44):4979–4988. DOI: 10.3748/wjg.v24.i44.4979.
Nguyen D., Samson S.L., Reddy V.T., Gonzalez E.V., Sekhar R.V. Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione. Aging Cell. 2013;12(3):415–425.
Nie T., Zou W., Meng Z., Wang L., Ying T., Cai X., Wu J., Zheng Y., Hu B. Bioactive Iridium Nanoclusters with Glutathione Depletion Ability for Enhanced Sonodynamic-Triggered Ferroptosis-Like Cancer Cell Death. Adv Mater. 2022;34(45).
Oestreicher J., Morgan B. Glutathione: subcellular distribution and membrane transport. Biochem Cell Biol. 2019;97(3):270–289. DOI: 10.1139/bcb-2018-0189.
Oliver J.M., Albertini D.F., Berlin R.D. Effects of glutathione-oxidizing agents on microtubule assembly and microtubule-dependent surface properties of human neutrophils. J Cell Biol. 1976;71(3):921–932.
Pallardó F.V., Markovic J., García J.L., Viña J. Role of nuclear glutathione as a key regulator of cell proliferation. Mol Asp Med. 2009;30:77–85.
Poornima K., Cariappa M., Asha K., Kedilaya H.P., Nandini M. Oxidant and antioxidant status in vegetarians and fish eaters. Indian J Clin Biochem. 2003;18:197–205.
Razavi Zade M., Telkabadi M.H., Bahmani F., Salehi B., Farshbaf S., Asemi Z. The effects of DASH diet on weight loss and metabolic status in adults with non-alcoholic fatty liver disease: A randomized clinical trial. Liver Int. 2016;36:563–571.
Richie J.P., Jr., Nichenametla S., Neidig W., Calcagnotto A., Haley J.S., Schell T.D., Muscat J.E. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur. J. Nutr. 2015;54:251–263. DOI: 10.1007/s00394-014-0706-z.
Sekhar R.V., Patel S.G., Guthikonda A.P., Reid M., Balasubramanyam A., Taffet G.E., Jahoor F. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011;94:847–853. DOI: 10.3945/ajcn.110.003483.
Schwartz J.L., Shklar G. Glutathione inhibits experimental oral carcinogenesis, p53 expression, and angiogenesis. Nutr Cancer. 1996;26:229–236.
Schmitt B., Vicenzi M., Garrel C., Denisb F.M. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 2015;6:198–205.
Sengupta R., Coppo L., Mishra P., Holmgren A. Glutathione-glutaredoxin is an efficient electron donor system for mammalian p53R2-R1-dependent ribonucleotide reductase. J Biol Chem. 2019;294(34):12708–12716. DOI: 10.1074/jbc.RA119.008752.
Shimizu H., Kiyohara Y., Kato I., Kitazono T., Tanizaki Y., Kubo M., Ueno H., Ibayashi S., Fujishima M., Iida M. Relationship between plasma glutathione levels and cardiovascular disease in a defined population: The Hisayama study. Stroke. 2004;35:2072–2077.
Short S., Merkel B.J., Caffrey R., McCoy K.L. Defective antigen processing correlates with a low level of intracellular glutathione. Eur J Immunol. 1996;26(12):3015–3020.
Sido B., Braunstein J., Breitkreutz R., Herfarth C., Meuer S.C. Thiol-mediated redox regulation of intestinal lamina propria T lymphocytes. J Exp Med. 2000;192(6):907–912.
Silvagno F., Vernone A., Pescarmona G.P. The role of glutathione in protecting against the severe inflammatory response triggered by COVID-19. Antioxidants. 2020;9:624. DOI: 10.3390/antiox9070624.
Stewart A.N., Glaser E.P., Mott C.A., Bailey W.M., Sullivan P.G., Patel S.P., Gensel J.C. Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury. J Neurotrauma. 2022;39(15-16):1075–1089.
Su Z., Yang Z., Xu Y., Chen Y., Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Molecular Cancer. 2015;14(1):48. DOI: 10.1186/s12943-015-0321-5.
Witschi A., Reddy S., Stofer B., Lauterburg B.H. The systemic availability of oral glutathione. Eur. J. Clin. Pharmacol. 1992;43:667–669
Copyright (c) 2024 Russian Biomedical Research
This work is licensed under a Creative Commons Attribution 4.0 International License.
