Review
The chemistry and biological activities of N-acetylcysteine

https://doi.org/10.1016/j.bbagen.2013.04.016Get rights and content

Highlights

  • The chemistry of N-acetylcysteine (NAC) is reviewed.

  • NAC can detoxify oxidizing radicals and bind redox-active metal ions.

  • NAC is a precursor of cysteine thus maintaining GSH intracellular levels.

  • NAC can efficiently reduce disulfide bonds in proteins thus altering their structures.

  • Not all mechanisms underlying the biological activities of NAC are already clear.

Abstract

Background

N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia–reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders.

Scope of review

The mechanisms underlying the therapeutic and clinical applications of NAC are complex and still unclear. The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its recognized biological activities and chemistry.

Major conclusions

The antioxidative activity of NAC as of other thiols can be attributed to its fast reactions with radical dotOH, radical dotNO2, CO3radical dot and thiyl radicals as well as to restitution of impaired targets in vital cellular components. NAC reacts relatively slowly with superoxide, hydrogen-peroxide and peroxynitrite, which cast some doubt on the importance of these reactions under physiological conditions. The uniqueness of NAC is most probably due to efficient reduction of disulfide bonds in proteins thus altering their structures and disrupting their ligand bonding, competition with larger reducing molecules in sterically less accessible spaces, and serving as a precursor of cysteine for GSH synthesis.

General significance

The outlined reactions only partially explain the diverse biological effects of NAC, and further studies are required for determining its ability to cross the cell membrane and the blood–brain barrier as well as elucidating its reactions with components of cell signaling pathways.

Introduction

N-acetylcysteine (also known as N-acetyl cysteine, N-acetyl-l-cysteine or NAC) has been in clinical practice for several decades. NAC has been used as a mucolytic agent and for the treatment of numerous disorders such as acetaminophen (paracetamol) intoxication, doxorubicin-induced cardiotoxicity, stable angina pectoris, ischemia–reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, radio-contrast-induced nephropathy, heavy metal toxicity and psychiatric disorders including schizophrenia, bipolar disorder and addiction ([1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12] for reviews).

NAC, the acetylated precursor of the amino acid l-cysteine, is pharmaceutically available either intravenously, orally, or by inhalation. NAC has relatively low toxicity and is associated with mild side effects such as nausea, vomiting, rhinorrhea, pruritus and tachycardia [4]. The terminal half-life of NAC after a single intravenous administration is 5.6 h where 30% of the drug is cleared by renal excretion [13]. The relatively low bioavailability of NAC (below 5% [13], [14], [15]) is thought to be associated with its N-deacetylation in the intestinal mucosa and first pass metabolism in the liver. The plasma is a rather pro-oxidizing milieu and, therefore, redox exchange reactions between NAC, cystine and cysteine proteins in the plasma produce NAC–cysteine, NAC–NAC and cysteine [16], [17]. The latter can cross the epithelial cell membrane and sustain the synthesis of glutathione (GSH), which is the ubiquitous source of the thiol pool in the body and an important antioxidant involved in numerous physiological processes [18], [19], [20]. These include detoxification of electrophilic xenobiotics, modulation of redox regulated signal transduction, regulation of immune response, prostaglandin and leukotriene metabolism, antioxidant defense, neurotransmitter signaling and modulation of cell proliferation ([19] for a review). The synthesis of GSH is tightly regulated at various levels and is kept at the mM concentration range [21]. Hence, the notion that the physiologic functions and therapeutic effects of NAC are largely associated with maintaining the levels of intracellular GSH is reasonable, and it is often difficult to discern the direct effect of NAC from those related to GSH.

The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its chemical features and recognized biological activities. For simplicity and practicality the various proposed mechanisms underlying NAC effects, which are presented here in their respective context, are not necessarily mutually exclusive but might operate concurrently.

Section snippets

The chemistry of NAC

NAC is a derivative of cysteine with an acetyl group attached to its nitrogen atom and like most thiols (RSH) can be oxidized by a large variety of radicals and also serve as a nucleophile (electron pair donor). The reactivity of thiolate anions (RS) towards nitrogen dioxide (radical dotNO2), carbon trioxide ion (CO3radical dot), azide (radical dotN3) or superoxide exceeds that of RSH with the exception of hydroxyl radical (radical dotOH), which efficiently abstracts H-atom from RSH [22]. RS reactivity towards non-radical oxidants,

Biological activities of NAC

NAC has been shown to interact with various metabolic pathways including, but not limited to, regulation of cell cycle and apoptosis; carcinogenesis and tumor progression; mutagenesis; gene expression and signal transduction; immune-modulation; cytoskeleton and trafficking; and mitochondrial functions [2]. As presented herein, the GSH-independent mechanisms underlying NAC activity are only partially understood. Furthermore, since the reactions of NAC with various ROS as well as reactive

Clinical caveats implied by the effects of NAC

Although NAC is traditionally considered as an antioxidant with proven benefits in various clinical conditions and experimental models, it is also implicated in some deleterious processes both in vitro and in vivo. Autoxidation of thiols in the presence of redox-active transition metals can lead to biological damage via the thiol oxidation by the metal ion (reaction (20)) followed by the generation of superoxide (reactions (3), (4), (21)), H2O2 (reaction (22)) and radical dotOH (reaction (23)) [257].RS + Mn

Concluding remarks

The molecular mechanisms by which NAC exerts its diverse effects are complex and still unclear. NAC has been shown to interact with numerous biochemical pathways. Its main mechanism involves serving as a precursor of cysteine and replenishing cellular GSH levels. Additional mechanisms include scavenging of radical dotOH, radical dotNO2, CO3radical dot and thiyl radicals as well as detoxification of semiquinones, HOCl, HNO and heavy metals. Importantly, under physiological conditions NAC does not react with NO, superoxide, H2O2

Acknowledgements

This work has been supported by the National Health and Medical Research Council of Australia, Simons Autism Foundation, CRC for Mental Health, Rotary Health, an Alfred Deakin Postdoctoral Research Fellowship (OMD) and by the Israel Science Foundation (Grant No. 1477).

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