N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why

References

• Hurst GA, Shaw PB, LeMaistre CA. Laboratory and clinical evaluation of the mucolytic properties of acetylcysteine. Am Rev Respir Dis. 1967;96(5):962–970.
   PubMedGoogle Scholar
• Prescott LF. New approaches in managing drug overdosage and poisoning. Br Med J (Clin Res Ed). 1983;287(6387):274–276.
   PubMedGoogle Scholar
• Balsamo R, Lanata L, Egan CG. Mucoactive drugs. Eur Respir Rev. 2010;19(116):127–133.
   PubMedGoogle Scholar
• Whitehouse LW, Wong LT, Paul CJ, et al. Postabsorption antidotal effects of N-acetylcysteine on acetaminophen-induced hepatotoxicity in the mouse. Can J Physiol Pharmacol. 1985;63(5):431–437.
   PubMed Web of Science ®Google Scholar
• Dodd S, Dean O, Copolov DL, et al. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther. 2008;8(12):1955–1962.
   PubMed Web of Science ®Google Scholar
• Vanderbist F, Maes P, Nève J. In vitro comparative assessment of the antioxidant activity of nacystelyn against three reactive oxygen species. Arzneimittelfor-schung. 1996;46(8):783–788.
   Google Scholar
• Kondo H, Takahashi M, Niki E. Peroxynitrite-induced hemolysis of human erythrocytes and its inhibition by antioxidants. FEBS Lett. 1997;413(2):236–238.
   PubMed Web of Science ®Google Scholar
• Sueishi Y, Hori M, Ishikawa M, et al. Scavenging rate constants of hydrophilic antioxidants against multiple reactive oxygen species. J Clin Biochem Nutr. 2014;54(2):67–74.
   PubMed Web of Science ®Google Scholar
• Ates B, Abraham L, Ercal N. Antioxidant and free radical scavenging properties of N-acetylcysteine amide (NACA) and comparison with N-acetylcysteine (NAC). Free Radic Res. 2008;42(4):372–377.
   PubMed Web of Science ®Google Scholar
• Sagristá ML, García AE, Africa De Madariaga M, et al. Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-L-cysteine and glutathione against free radical-induced lipid peroxidation. Free Radic Res. 2002;36(3):329–340.
   PubMed Web of Science ®Google Scholar
• Michelucci A, De Marco A, Guarnier FA, et al. Antioxidant treatment reduces formation of structural cores and improves muscle function in RYR1Y522S/WT mice. Oxid Med Cell Longev. 2017;2017:6792694.
   PubMedGoogle Scholar
• Dhanda S, Kaur S, Sandhir R. Preventive effect of N-acetyl-L-cysteine on oxidative stress and cognitive impairment in hepatic encephalopathy following bile duct ligation. Free Radic Biol Med. 2013;56:204–215.
   PubMed Web of Science ®Google Scholar
• Sandhir R, Kaur S, Dhanda S. N-acetyl-l-cysteine prevents bile duct ligation induced renal injury by modulating oxidative stress. Indian J Clin Biochem. 2017;32(4):411–419.
   PubMed Web of Science ®Google Scholar
• Ortiz MS, Forti KM, Suárez Martinez EB, et al. Effects of antioxidant N-acetylcysteine against paraquat-induced oxidative stress in vital tissues of mice. Int J Sci Basic Appl Res. 2016;26(1):26–46.
   PubMedGoogle Scholar
• Zembron-Lacny A, Slowinska-Lisowska M, Szygula Z, et al. The comparison of antioxidant and hematological properties of N-acetylcysteine and alpha-lipoic acid in physically active males. Physiol Res. 2009;58(6):855–861.
   PubMed Web of Science ®Google Scholar
• Zhang L, Xu S, Huang Q, et al. N-acetylcysteine attenuates the cuprizone-induced behavioral changes and oligodendrocyte loss in male C57BL/7 mice via its anti-inflammation actions. J Neurosci Res. 2018;96(5):803–816.
   PubMed Web of Science ®Google Scholar
• Samuni Y, Goldstein S, Dean OM, et al. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830(8):4117–4129.
   PubMed Web of Science ®Google Scholar
• Soldini D, Zwahlen H, Gabutti L, et al. Pharmacokine-tics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. Eur J Clin Pharmacol. 2005;60(12):859–864.
   PubMed Web of Science ®Google Scholar
• Winterbourn CC. Revisiting the reactions of superoxide with glutathione and other thiols. Arch Biochem Biophys. 2016;595:68–71.
   PubMed Web of Science ®Google Scholar
• Trujillo M, Radi R. Peroxynitrite reaction with the reduced and the oxidized forms of lipoic acid: new insights into the reaction of peroxynitrite with thiols. Arch Biochem Biophys. 2002;397(1):91–98.
   PubMed Web of Science ®Google Scholar
• Carballal S, Bartesaghi S, Radi R. Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite. Biochim Biophys Acta. 2014;1840(2):768–780.
   PubMed Web of Science ®Google Scholar
• Hoy A, Leininger-Muller B, Kutter D, et al. Growing significance of myeloperoxidase in non-infectious diseases. Clin Chem Lab Med. 2002;40(1):2–8.
   PubMed Web of Science ®Google Scholar
• O’Donnell C, Newbold P, White P, et al. 3-Chlorotyrosine in sputum of COPD patients: relationship with airway inflammation. COPD. 2010;7(6):411–417.
   PubMedGoogle Scholar
• Yuan S, Hollinger M, Lachowicz-Scroggins ME, et al. Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci Transl Med. 2015;7(276):276ra27.
   PubMed Web of Science ®Google Scholar
• Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J. 1994;7(3):431–436.
   PubMed Web of Science ®Google Scholar
• Persinger RL, Poynter ME, Ckless K, et al. Molecular mechanisms of nitrogen dioxide induced epithelial injury in the lung. Mol Cell Biochem. 2002;2002:71–80.
   Google Scholar
• Storkey C, Davies MJ, Pattison DI. Reevaluation of the rate constants for the reaction of hypochlorous acid (HOCl) with cysteine, methionine, and peptide derivatives using a new competition kinetic approach. Free Radic Biol Med. 2014;73:60–66.
   PubMed Web of Science ®Google Scholar
• Müller B, Oske M, Hochscheid R, et al. Effect of N-acetylcysteine treatment on NO2-impaired type II pneumocyte surfactant metabolism. Eur J Clin Invest. 2001;31(2):179–188.
   PubMed Web of Science ®Google Scholar
• Siddiqui MR, Wabaidur SM, Ola MS, et al. High-throughput UPLC-MS method for the determination of N-acetyl-l-cysteine: application in Tissue Distribution Study in Wistar rats. J Chromatogr Sci. 2016;54(7):1244–1252.
   PubMed Web of Science ®Google Scholar
• Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res. 1996;145(5):532–541.
   PubMed Web of Science ®Google Scholar
• Kimoto E, Tanaka H, Gyotoku J, et al. Enhancement of antitumor activity of ascorbate against Ehrlich ascites tumor cells by the copper:glycylglycylhistidine complex. Cancer Res. 1983;43(2):824–828.
   PubMed Web of Science ®Google Scholar
• Neuzil J, Thomas SR, Stocker R. Requirement for, promotion, or inhibition by alpha-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation. Free Radic Biol Med. 1997;22(1–2):57–71.
   PubMed Web of Science ®Google Scholar
• Viña J, Saez GT, Wiggins D, et al. The effect of cysteine oxidation on isolated hepatocytes. Biochem J. 1983;212(1):39–44.
   PubMed Web of Science ®Google Scholar
• Saez G, Thornalley PJ, Hill HA, et al. The production of free radicals during the autoxidation of cysteine and their effect on isolated rat hepatocytes. Biochim Biophys Acta. 1982;719(1):24–31.
   PubMedGoogle Scholar
• Viña J, Hems R, Krebs HA. Maintenance of glutathione content is isolated hepatocyctes. Biochem J. 1978;170(3):627–630.
   PubMed Web of Science ®Google Scholar
• Wu MS, Lien GS, Shen SC, et al. N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol Carcinog. 2014;53(Suppl1):E119–E129.
   Web of Science ®Google Scholar
• Zheng J, Lou JR, Zhang XX, et al. N-acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death. Cancer Lett. 2010;298(2):186–194.
   PubMed Web of Science ®Google Scholar
• Zheng Z, Shetty K. Solid-state bioconversion of phenolics from cranberry pomace and role of Lentinus edodes beta-glucosidase. J Agric Food Chem. 2000;48(3):895–900.
   PubMed Web of Science ®Google Scholar
• Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711–760.
   PubMed Web of Science ®Google Scholar
• Deponte M. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta. 2013;1830(5):3217–3266.
   PubMed Web of Science ®Google Scholar
• Vistoli G, De Maddis D, Cipak A, et al. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res. 2013;47(Suppl1):3–27.
   Web of Science ®Google Scholar
• Aldini G, Carini M, Yeum KJ, et al. Novel molecular approaches for improving enzymatic and nonenzymatic detoxification of 4-hydroxynonenal: toward the discovery of a novel class of bioactive compounds. Free Radic Biol Med. 2014;69:145–156.
   PubMed Web of Science ®Google Scholar
• Aldini G, Vistoli G, Stefek M, et al. Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res. 2013;47(Suppl1):93–137.
   Web of Science ®Google Scholar
• Giustarini D, Colombo G, Garavaglia ML, et al. Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells. Free Radic Biol Med. 2017;112:360–375.
   PubMed Web of Science ®Google Scholar
• Asher BF, Guilford FT. Oxidative stress and low glutathione in common ear, nose, and throat conditions: a systematic review. Altern Ther Health Med. 2016;22(5):44–50.
   PubMed Web of Science ®Google Scholar
• Homma T, Fujii J. Application of glutathione as anti-oxidative and anti-aging drugs. Curr Drug Metab. 2015;16(7):560–571.
   PubMed Web of Science ®Google Scholar
• Morris G, Anderson G, Dean O, et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol. 2014;50(3):1059–1084.
   PubMed Web of Science ®Google Scholar
• Gu F, Chauhan V, Chauhan A. Glutathione redox imbalance in brain disorders. Curr Opin Clin Nutr Metab Care. 2015;18(1):89–95.
   PubMed Web of Science ®Google Scholar
• Gould NS, Day BJ. Targeting maladaptive glutathione responses in lung disease. Biochem Pharmacol. 2011;81(2):187–193.
   PubMed Web of Science ®Google Scholar
• Kalsi SS, Dargan PI, Waring WS, et al. A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose. Open Access Emerg Med. 2011;3:87–96.
   PubMedGoogle Scholar
• Anders MW, Dekant W. Aminoacylases. Adv Pharmacol. 1994;27:431–448.
   PubMedGoogle Scholar
• Zhang H, Su W, Ying Z, et al. N-acetylcysteine attenuates intrauterine growth retardation-induced hepatic damage in suckling piglets by improving glutathione synthesis and cellular homeostasis. Eur J Nutr. 2018;57(1):327–338.
   PubMed Web of Science ®Google Scholar
• Arfsten DP, Johnson EW, Wilfong ER, et al. Distribution of radio-labeled N-acetyl-L-cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage. Cutan Ocul Toxicol. 2007;26(2):113–134.
   PubMed Web of Science ®Google Scholar
• Arfsten D, Johnson E, Thitoff A, et al. Impact of 30-day oral dosing with N-acetyl-L-cysteine on Sprague-Dawley rat physiology. Int J Toxicol. 2004;23(4):239–247.
   PubMed Web of Science ®Google Scholar
• Pendyala L, Creaven PJ. Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial. Cancer Epidemiol Biomarkers Prev. 1995;4(3):245–251.
   PubMed Web of Science ®Google Scholar
• Meyer A, Buhl R, Kampf S, et al. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respir Crit Care Med. 1995;152(3):1055–1060.
   PubMed Web of Science ®Google Scholar
• Nagy P. Kinetics and mechanisms of thiol-disulfide exchange covering direct substitution and thiol oxidation-mediated pathways. Antioxid Redox Signal. 2013;18(13):1623–1641.
   PubMed Web of Science ®Google Scholar
• Noszál B, Visky D, Kraszni M. Population, acid–base, and redox properties of N-acetylcysteine conformers. J Med Chem. 2000;43(11):2176–2182.
   PubMed Web of Science ®Google Scholar
• Parker AJ, Kharasch N. Derivatives of sulfenic acids. XXXVI. The ionic scission of the sulfur–sulfur Bond 1 part 1. J Am Chem Soc. 1960;82:4.
   Web of Science ®Google Scholar
• McGuckin MA, Thornton DJ, Whitsett JA, et al. Mucins and Mucus A2 – Mestecky, Jiri. Mucosal immunology. 4th ed. Boston: Academic Press; 2015. p. 231–250 (Chapter 14).
   Google Scholar
• Sheffner AL, Medler EM, Jacobs LW, et al. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis. 1964;90:721–729.
   PubMed Web of Science ®Google Scholar
• Janssen B, Hohenadel D, Brinkkoetter P, et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes. 2005;54(8):2320–2327.
   PubMed Web of Science ®Google Scholar
• Radtke KK, Coles LD, Mishra U, et al. Interaction of N-acetylcysteine and cysteine in human plasma. J Pharm Sci. 2012;101(12):4653–4659.
   PubMed Web of Science ®Google Scholar
• Zhou J, Coles LD, Kartha RV, et al. Intravenous administration of stable-labeled N-acetylcysteine demonstrates an indirect mechanism for boosting glutathione and improving redox status. J Pharm Sci. 2015;104(8):2619–2626.
   PubMed Web of Science ®Google Scholar
• Turell L, Radi R, Alvarez B. The thiol pool in human plasma: the central contribution of albumin to redox processes. Free Radic Biol Med. 2013;65:244–253.
   PubMed Web of Science ®Google Scholar
• Colombo G, Clerici M, Giustarini D, et al. Redox albuminomics: oxidized albumin in human diseases. Antioxid Redox Signal. 2012;17(11):1515–1527.
   PubMed Web of Science ®Google Scholar
• Carballal S, Alvarez B, Turell L, et al. Sulfenic acid in human serum albumin. Amino Acids. 2007;32(4):543–551.
   PubMed Web of Science ®Google Scholar
• Aldini G, Regazzoni L, Orioli M, et al. A tandem MS precursor-ion scan approach to identify variable covalent modification of albumin Cys34: a new tool for studying vascular carbonylation. J Mass Spectrom. 2008;43(11):1470–1481.
   PubMed Web of Science ®Google Scholar
• Nagumo K, Tanaka M, Chuang VT, et al. Cys34-cysteinylated human serum albumin is a sensitive plasma marker in oxidative stress-related chronic diseases. PLoS One. 2014;9(1):e85216.
   PubMed Web of Science ®Google Scholar
• Regazzoni L, Del Vecchio L, Altomare A, et al. Human serum albumin cysteinylation is increased in end stage renal disease patients and reduced by hemodialysis: mass spectrometry studies. Free Radic Res. 2013;47(3):172–180.
   PubMed Web of Science ®Google Scholar
• Carballal S, Radi R, Kirk MC, et al. Sulfenic acid formation in human serum albumin by hydrogen peroxide and peroxynitrite. Biochemistry. 2003;42(33):9906–9914.
   PubMed Web of Science ®Google Scholar
• Harada D, Anraku M, Fukuda H, et al. Kinetic studies of covalent binding between N-acetyl-L-cysteine and human serum albumin through a mixed-disulfide using an N-methylpyridinium polymer-based column. Drug Metab Pharmacokinet. 2004;19(4):297–302.
   PubMedGoogle Scholar
• Fu XY, Cate SA, Chen JM, et al. Effect of N-acetyl-L-cysteine on cysteine redox status in patients with thrombotic thrombocytopenic purpura: protein disulfide bound cysteine as a biomarker of oxidative stress. Blood. 2015;126(23):1044.
   Web of Science ®Google Scholar
• He X, Wu X, Shi W, et al. Comparison of N-acetylcysteine and cysteine in their ability to replenish intracellular cysteine by a specific fluorescent probe. Chem Commun (Camb). 2016;52(60):9410–9413.
   PubMed Web of Science ®Google Scholar
• Moreno ML, Escobar J, Izquierdo-Álvarez A, et al. Disulfide stress: a novel type of oxidative stress in acute pancreatitis. Free Radic Biol Med. 2014;70:265–277.
   PubMed Web of Science ®Google Scholar