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Article

N-Acetyl-Cysteine Regenerates Albumin Cys34 by a Thiol-Disulfide Breaking Mechanism: An Explanation of Its Extracellular Antioxidant Activity

1
Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
2
Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy
3
Department of Clinical Sciences and Community Health, Cardiovascular Section, Università degli Studi di Milano, Via della Commenda 19, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(5), 367; https://doi.org/10.3390/antiox9050367
Received: 30 March 2020 / Revised: 22 April 2020 / Accepted: 27 April 2020 / Published: 28 April 2020
(This article belongs to the Special Issue Commemorative Issue of Antioxidants Dedicated to Peter Eckl)
In the present paper, the extracellular antioxidant activity of N-acetyl-cysteine (NAC) is explained by considering its ability to regenerate the free form of albumin Cys34 by breaking the disulfide bond of the cysteinylated form (HSA-Cys). NAC’s capability to regenerate albumin Cys34 (HSA-SH) was studied by MS intact protein analysis in human plasma and in a concentration range of NAC easily achievable after oral and i.v. administration (5–50 µg/mL). NAC dose-dependently broke the HSA-Cys bond to form the dimer NAC-Cys thus regenerating Cys34, whose reduced state was maintained for at least 120 min. Cys was faster in restoring Cys34, according to the reaction constant determined with the glutathione disulfide (GSSG) reaction, but after 60 min the mixed disulfide HSA-Cys turned back due to the reaction of the dimer Cys-Cys with Cys34. The explanation for the different rate exchanges between Cys-Cys and Cys-NAC with Cys34 was given by molecular modeling studies. Finally, the Cys34 regenerating effect of NAC was related to its ability to improve the total antioxidant capacity of plasma (TRAP assay). The results well indicate that NAC greatly increases the plasma antioxidant activity and this effect is not reached by a direct effect but through the regenerating effect of Cys34. View Full-Text
Keywords: N-acetyl-cysteine; albumin; Cys34; cysteine; antioxidant; plasma N-acetyl-cysteine; albumin; Cys34; cysteine; antioxidant; plasma
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MDPI and ACS Style

Altomare, A.; Baron, G.; Brioschi, M.; Longoni, M.; Butti, R.; Valvassori, E.; Tremoli, E.; Carini, M.; Agostoni, P.; Vistoli, G.; Banfi, C.; Aldini, G. N-Acetyl-Cysteine Regenerates Albumin Cys34 by a Thiol-Disulfide Breaking Mechanism: An Explanation of Its Extracellular Antioxidant Activity. Antioxidants 2020, 9, 367. https://doi.org/10.3390/antiox9050367

AMA Style

Altomare A, Baron G, Brioschi M, Longoni M, Butti R, Valvassori E, Tremoli E, Carini M, Agostoni P, Vistoli G, Banfi C, Aldini G. N-Acetyl-Cysteine Regenerates Albumin Cys34 by a Thiol-Disulfide Breaking Mechanism: An Explanation of Its Extracellular Antioxidant Activity. Antioxidants. 2020; 9(5):367. https://doi.org/10.3390/antiox9050367

Chicago/Turabian Style

Altomare, Alessandra; Baron, Giovanna; Brioschi, Maura; Longoni, Martina; Butti, Riccardo; Valvassori, Edoardo; Tremoli, Elena; Carini, Marina; Agostoni, Piergiuseppe; Vistoli, Giulio; Banfi, Cristina; Aldini, Giancarlo. 2020. "N-Acetyl-Cysteine Regenerates Albumin Cys34 by a Thiol-Disulfide Breaking Mechanism: An Explanation of Its Extracellular Antioxidant Activity" Antioxidants 9, no. 5: 367. https://doi.org/10.3390/antiox9050367

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