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

Figures & data

Figure 1. (a) Chemical structures of Cys and of NAC. (b) The mucolytic action of NAC is due to its ability to break the disulphide bridges of the high-molecular-weight glycoproteins in the mucus, resulting in reduced viscosity. (c) NAC for the treatment of acetaminophen poisoning. NAC acts by replenishing hepatic GSH, which is the main endogenous nucleophilic peptide able to neutralise N-acetyl-p-benzoquinone imine (NAPQI), the electrophilic metabolite of acetaminophen. Paracetamol is metabolised forming the electrophilic metabolite (NAPQI) which is detoxified by GSH. In the case of GSH depletion, NAPQI reacts with proteins forming adducts which can induce cell damage or immune response. NAC acts by replenishing the GSH pool as a precursor of Cys, the building block and the rate-limiting step in glutathione synthesis. NAC is converted to Cys through a deacetylation reaction catalysed by acylase.

Table 1. Reaction rate constants of NAC, Cys, GSH, and endogenous enzymatic antioxidants toward the main oxidant species.

Oxidant	Antioxidant	K (M^−1 s^−1)	Reference
H2O2
	NAC	0.16	[66]
	GSH	0.89	[66]
	Cys	2.9	[66]
	Peroxiredoxins	1–4 × 10^7	[66]
ONOOH
	NAC	415 ± 10	[20]
	GSH	1360 ± 60	[20]
	Cys	4500	[20]
	Peroxiredoxins	1 × 10^6−1 × 10^7	[67]
O2^•−
	NAC	68	[68]
	GSH	200	[69]
	Cys	15	[68]
	Superoxide dismutase	2.3 × 10^9	[70]
HO^•
	NAC	1.36 × 10^10	[71]
	GSH	1.64 × 10^10	[8]
	Cys	5.35 ± 0.2 × 10^9	[72]
	Uric acid	9.52 × 10^9	[8]
HO(X)
	NAC	0.29 ± 0.04 × 10^8	[27]
	GSH	1.2 ± 0.2 × 10^8	[27]
	Cys	3.6 ± 0.5 × 10^8	[27]
NO2
	NAC	1 × 10^7	Estimated by [17]
	GSH	2 × 10^7	[73]
	Cys	6 × 10^7	[73]

Figure 2. Antioxidant and disulphide breaking activity of NAC in lung disease characterised by an inflammatory condition. The oxidative burst causes the oxidation of internal cysteine of mucins, generating disulphide cross-links between internal cysteine domains. The resulting heavily cross-linked mucus is not easily transported and accumulates to cause airflow obstruction, atelectasis, and lung infection [24]. NAC is a mucolytic agent able to reduce the heavily cross-linked mucus. When Cys and GSH are depleted following the inflammatory condition, NAC can act as a direct antioxidant of some oxidant species such as HOX and NO₂.

Figure 3. Overview of the antioxidant action of NAC. The antioxidant effect is due to indirect (GSH synthesis) and direct antioxidant activity, as well as disulphide breaking activity. The indirect activity refers to the ability of NAC to act as a GSH precursor, which in turn is a well-known direct antioxidant and a substrate of several antioxidant enzymes. When an oxidative stress status depletes the SH pools, NAC can act as direct scavenger of some oxidants such as NO(X) and NO₂. NAC breaks thiolated proteins thus releasing free thiols, which have a better antioxidant activity than NAC and boost the synthesis of GSH and reduced proteins, which in some cases, such as for mercaptoalbumin, have an important direct antioxidant activity.

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