The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid

doi:10.1016/0891-5849(89)90066-X

Free Radical Biology and Medicine

Volume 6, Issue 6, 1989, Pages 593-597

https://doi.org/10.1016/0891-5849(89)90066-X Get rights and content

Abstract

N-acetylcysteine has been widely used as an antioxidant in vivo and in vitro. Its reaction with four oxidant species has therefore been examined. N-acetylcysteine is a powerful scavenger of hypochlorous acid (HOCl); low concentrations are able to protect α₁-antiproteinase against inactivation by HOCl. N-acetylcysteine also reacts with hydroxyl radical with a rate constant of 1.36 × 10¹⁰ M⁻¹s⁻¹, as determined by pulse radiolysis. It also reacts slowly with H₂O₂, but no reaction of N-acetylcysteine with superoxide (O₂⁻) could be detected within the limits of our assay procedures.

References (26)

I.A. Cotgreave et al.
N-acetylcysteine and glutathione-dependent protective effect of PZ51 (Ebselen) against diquat-induced cytotoxicity in isolated hepatocytes
Biochem. Pharmacol.
(1987)
J.O. Miners et al.
Mechanism of action of paracetamol protective agents in mice in vivo
Biochem. Pharmacol.
(1984)
M. Wasil et al.
Biologically-significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by some anti-inflammatory drugs
Biochem. Pharmacol.
(1987)
O.I. Aruoma et al.
The scavenging of oxidants by sulphasalazine and its metabolites
Biochem. Pharmacol.
(1987)
B. Halliwell
Use of desferrioxamine as a probe for iron-dependent formation of hydroxyl radicals. Evidence for a direct reaction between desferal and the superoxide radical
Biochem. Pharmacol.
(1985)
J.M. McCord et al.
Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)
J. Biol. Chem.
(1969)
W.F. Beyer et al.
Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions
Analyt. Biochem.
(1987)
G.L. Ellman
Tissue sulfhydryl groups
Arch. Biochem. Biophys.
(1959)
R.A. Clark et al.
Myeloperoxidase-catalyzed inactivation of α₁-protease inhibitor by human neutrophils
J. Biol. Chem.
(1981)
A.F. Junod et al.
Comparative study on the selenium- and N-acetylcysteine-related effects on the toxic actions of hyperoxia, paraquat and the enzyme reaction hypoxanthine-xanthine oxidase in cultured endothelial cells
Agents Actions
(1987)

G.R. Gernard et al.

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function

J. Clin. Invest.

(1984)

P. Moldeus et al.

Lung protection by a thiol-containing antioxidant: N-acetylcysteine

Respiration

(1986)

I. Ziment

Acetylcysteine: a drug with an interesting past and a fascinating future

Respiration

(1986)

Cited by (1664)

Proteasome inhibitors induce apoptosis by superoxide anion generation via NADPH oxidase 5 in human neuroblastoma SH-SY5Y cells
2024, Journal of Pharmacological Sciences
The ubiquitin-proteasome system (UPS) is a major proteolytic system that plays an important role in the regulation of various cell processes, such as cell cycle, stress response, and transcriptional regulation, especially in neurons, and dysfunction of UPS is considered to be a cause of neuronal cell death in neurodegenerative diseases. However, the mechanism of neuronal cell death caused by UPS dysfunction has not yet been fully elucidated.
In this study, we investigated the mechanism of neuronal cell death induced by proteasome inhibitors using human neuroblastoma SH-SY5Y cells. Z-Leu-D-Leu-Leu-al (MG132), a proteasome inhibitor, induced apoptosis in SH-SY5Y cells in a concentration- and time-dependent manner. Antioxidants N-acetylcysteine and EUK-8 attenuated MG132-induced apoptosis. Apocynin and diphenyleneiodonium, inhibitors of NADPH oxidase (NOX), an enzyme that produces superoxide anions, also attenuated MG132-induced apoptosis. It was also found that MG132 treatment increased the expression of NOX5, a NOX family member, and that siRNA-mediated silencing of NOX5 and BAPTA-AM, which inhibits NOX5 by chelating calcium, suppressed MG132-induced apoptosis and production of reactive oxygen species in SH-SY5Y cells.
These results suggest that MG132 induces apoptosis in SH-SY5Y cells through the production of superoxide anion by NOX5.
A novel impedimetric sensor based on N-acetyl-L-cysteine for the determination of hydroxyl radicals in cell cultures in vitro
2024, Talanta
We report a novel impedimetric sensor based on a graphite electrode impregnated with polyethylene and paraffin under vacuum (IGE) modified with electrochemically deposited gold and a self-assembled monolayer of N-acetyl-L-cysteine (NAC/Au/IGE) for selective and sensitive determination of extracellular hydroxyl radicals (OH^•) generated by living cells. The application of a sulphur-containing molecule oxidized by OH^• predicts the high selectivity of the sensor, and the utilization of the non-faradaic impedance spectroscopy for recording an analytical response makes it possible to achieve superior sensitivity with a detection limit of 0.01 nM and a linear dynamic range of 0.08–8 nM. Meanwhile, NAC/Au/IGE demonstrated a strong potential of detecting OH^• generated by biological objects via successful determination of extracellular hydroxyl radicals generated by normal fibroblast cells and prostate carcinoma cells.
N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo
2023, Toxicology and Applied Pharmacology
The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl₂)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl₂ exposure and evaluating antioxidant treatments.
The toxicological responses were analyzed in Cl₂-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects.
In Cl₂-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl₂ resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl₂ exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models.
In conclusion, the establishment of a pig model for Cl₂-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl₂ injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl₂-induced lung injury.
DBP induced autophagy and necrotic apoptosis in HepG2 cells via the mitochondrial damage pathway
2023, Food and Chemical Toxicology
Phthalate esters (PAEs) are widely present in human tissues and pose significant health risks. In this study, HepG2 cells were treated with 0.0625, 0.125, 0.25, 0.5 and 1 mM Dibutyl phthalate (DBP) for 48 h to investigate mitochondrial toxicity. The results showed that DBP caused mitochondrial damage, autophagy, apoptosis and necroptosis; Transcriptomics analysis identified that MAPK and PI3K were significant factors in the cytotoxic changes induced by DBP; N-Acetyl-L-cysteine (NAC), SIRT1 activator, ERK inhibitor, p38 inhibitor and ERK siRNA treatments counteracted the changes of SIRT1/PGC-1α and Nrf2 pathway-related proteins, autophagy and necroptotic apoptosis proteins induced by DBP. While PI3K and Nrf2 inhibitors exacerbated the changes in SIRT1/PGC-1α, Nrf2-associated proteins and autophagy and necroptosis proteins induced by DBP. In addition, the autophagy inhibitor 3-MA alleviated the increase in DBP-induced necroptosis proteins. These results suggested that DBP-induced oxidative stress activated the MAPK pathway, inhibited the PI3K pathway, which in turn inhibited the SIRT1/PGC-1α pathway and Nrf2 pathway, thereby causing cell autophagy and necroptosis.
N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer
2023, Cell Reports Medicine
A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CA^H1047R-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CA^H1047R breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.
Molecular mechanisms of ferroptosis and their involvement in brain diseases
2023, Pharmacology and Therapeutics
Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways.
Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation.
On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors.
Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors.
Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.

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Free Radical Biology and Medicine

Abstract

References (26)

N-acetylcysteine and glutathione-dependent protective effect of PZ51 (Ebselen) against diquat-induced cytotoxicity in isolated hepatocytes

Biochem. Pharmacol.

Mechanism of action of paracetamol protective agents in mice in vivo

Biochem. Pharmacol.

Biologically-significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by some anti-inflammatory drugs

Biochem. Pharmacol.

The scavenging of oxidants by sulphasalazine and its metabolites

Biochem. Pharmacol.

Use of desferrioxamine as a probe for iron-dependent formation of hydroxyl radicals. Evidence for a direct reaction between desferal and the superoxide radical

Biochem. Pharmacol.

Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)

J. Biol. Chem.

Assaying for superoxide dismutase activity: some large consequences of minor changes in conditions

Analyt. Biochem.

Tissue sulfhydryl groups

Arch. Biochem. Biophys.

Myeloperoxidase-catalyzed inactivation of α₁-protease inhibitor by human neutrophils

J. Biol. Chem.

Comparative study on the selenium- and N-acetylcysteine-related effects on the toxic actions of hyperoxia, paraquat and the enzyme reaction hypoxanthine-xanthine oxidase in cultured endothelial cells

Agents Actions

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function

J. Clin. Invest.

Lung protection by a thiol-containing antioxidant: N-acetylcysteine

Respiration

Acetylcysteine: a drug with an interesting past and a fascinating future

Respiration

Cited by (1664)

Proteasome inhibitors induce apoptosis by superoxide anion generation via NADPH oxidase 5 in human neuroblastoma SH-SY5Y cells

A novel impedimetric sensor based on N-acetyl-L-cysteine for the determination of hydroxyl radicals in cell cultures in vitro

N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo

DBP induced autophagy and necrotic apoptosis in HepG2 cells via the mitochondrial damage pathway

N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer

Molecular mechanisms of ferroptosis and their involvement in brain diseases

Original contributionThe antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid

Abstract

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

J. Biol. Chem.

Analyt. Biochem.

Arch. Biochem. Biophys.

J. Biol. Chem.

Comparative study on the selenium- and N-acetylcysteine-related effects on the toxic actions of hyperoxia, paraquat and the enzyme reaction hypoxanthine-xanthine oxidase in cultured endothelial cells

Agents Actions

Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function

J. Clin. Invest.

Lung protection by a thiol-containing antioxidant: N-acetylcysteine

Respiration

Acetylcysteine: a drug with an interesting past and a fascinating future

Respiration

Original contribution
The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid