N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency

doi:10.1016/j.coph.2007.04.005

Current Opinion in Pharmacology

Volume 7, Issue 4, August 2007, Pages 355-359

https://doi.org/10.1016/j.coph.2007.04.005 Get rights and content

Glutathione (GSH) deficiency is associated with numerous pathological conditions. Administration of N-acetylcysteine (NAC), a cysteine prodrug, replenishes intracellular GSH levels. NAC, best known for its ability to counter acetaminophen toxicity, is a safe, well-tolerated antidote for cysteine/GSH deficiency. NAC has been used successfully to treat GSH deficiency in a wide range of infections, genetic defects and metabolic disorders, including HIV infection and COPD. Over two-thirds of 46 placebo-controlled clinical trials with orally administered NAC have indicated beneficial effects of NAC measured either as trial endpoints or as general measures of improvement in quality of life and well-being of the patients.

Section snippets

Biochemistry and function

In vitro and in vivo studies have shown that NAC acts as a cysteine prodrug and a GSH precursor [15]. It can also reduce disulphide bonds in proteins [16, 17], scavenge free radicals [18] and bind metals to form complexes [19]. However, its principal use pharmacologically is to replenish the cysteine and GSH that are lost due to acetaminophen toxicity.

Chemically NAC is similar to cysteine. The presence of the acetyl moiety, however, reduces the reactivity of the thiol as compared with that of

In vivo metabolism

NAC's primary function in vivo is to supply cysteine necessary for GSH synthesis and replenishment. Consistent with this, pharmacokinetics studies have shown that NAC undergoes extensive first pass metabolism in the liver and kidneys resulting in very low concentrations of ‘free’ NAC in the plasma [22, 23] and virtually undectable levels of NAC in other body fluids such as broncho-alveolar lavage [24].

Orally delivered NAC is readily taken up in the stomach (low pH in the stomach makes the

NAC administration and toxicity

NAC has been administered orally, intravenously and topically (e.g. as aerosol). Topical delivery of NAC has not been shown to increase systemic NAC, cysteine or GSH levels. Further, aerosol delivery can result in NAC oxidation, which may have negative consequences [27]. Intravenous administration of NAC transiently increases plasma NAC to very high levels (during administration) and is known to cause adverse effects. Although clinical situations sometimes dictate the need for intravenous

NAC formulations

The best known NAC formulation in the US is Mucomyst™ (or the generic version thereof). Although it is commonly administered orally for the treatment of acetaminophen overdose, it has a strong, disagreeable flavour and therefore is usually mixed with a fruit juice or a soft drink before consumption. In contrast, NAC is produced and packaged in Europe in pill and capsule formulations, as well as in a variety of effervescent formulations (‘fizzy tabs’) that can be dissolved in water, juice or

Disease indications for NAC

Glutathione deficiency occurs frequently in many diseases because of a variety of factors that include viral protein-mediated GSH depletion (e.g. HIV Tat), uncontrolled inflammatory reactions and increased generation of free radicals [32, 33]. GSH deficiency may increase either the rate of disease progression or the severity of the disease symptoms. Alternatively, GSH deficiency may not contribute to the specific symptoms of the disease and is recognizable mainly by secondary symptoms such as

Conclusions/future directions

Oral administration of NAC, a safe, well-tolerated drug with no clinically significant adverse effects, has been shown to be beneficial in settings where GSH deficiency occurs, for example, HIV infection, CF and diabetes. Although many trials have been conducted, more are needed to further ascertain the effect of NAC in diseases associated with GSH deficiency.

In individual patients, the extent of GSH deficiency that develops may vary depending on the disease severity, patient diet and other

Conflict of interest

Two of the authors, Leonard A. Herzenberg and Leonore A. Herzenberg, have a loose working relationship with BioAdvantex Pharma Inc. (Mississauga, Ontario, Canada), a small privately held nutriceutical company that sells OTC oral N-acetylcysteine (NAC) produced to meet European GMP standards. The BioAdvantex market share is <1% of the overall North American market and non-existent elsewhere. BioAdvantex has sponsored two meetings that the Herzenbergs attended, has reimbursed travel for Leonore

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank Dr Rabindra Tirouvanziam for informative discussions and critical reading of this review. Studies here were supported by a grant (AI 566223) from the National Institutes of Health.

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