One of the only viable methods of increasing intracellular levels of the superantioxidant glutathione is supplementing with N-acetylcysteine (NAC), a prodrug for the amino acid cysteine.1

Deficiency of intracellular glutathione can worsen oxidative stress and accelerate cellular death in multiple diseases, including Alzheimer disease, Parkinson disease, liver disease, HIV/AIDS, cystic fibrosis, sickle cell anemia, and diabetes.2 Consequently, the potential impact of enhancing this compound in the body is tremendous.

Background

NAC is counted as one of the most important medications needed in a basic health system, according to the World Health Organization (WHO).3 

The WHO indicates NAC is essential for pulmonary and renal protection, antimicrobial uses, and psychiatry.3 NAC has been used as an antidote for acetaminophen toxicity.4 Pulmonologists have also used it as an effective inhaled mucolytic in patients with cystic fibrosis.4

Science

The conversion of NAC to cysteine is the rate-limiting step in the very complex synthesis of glutathione in the human cell.5 Multiple studies both in vitro and in vivo have demonstrated rapid, massive cellular death when an organism is starved of cysteine.5 However, the actual mechanism of cell death appears to be the loss of available glutathione.

NAC has been used with success in respiratory conditions for many years, but the way it works is not clear. Current literature suggests that the main action of NAC is that of a tissue-specific antioxidant. In both cystic fibrosis and chronic obstructive pulmonary disease (COPD), excessive infiltration of pro-inflammatory cytokines and lymphocytes trigger massive up-regulation of potent reactive oxidative species.6 

As the delicate tissues of the pulmonary alveoli are subjected to this toxic stimuli year after year, the body gradually loses its ability to compensate, and lung function declines.

Studies designed to increase intracellular glutathione by means of cysteine supplementation in these respiratory diseases have shown positive results. 

Patients with COPD taking an NAC supplement twice daily for 6 weeks have experienced a 6% improvement in forced vital capacity after exercise and overall endurance time and a 9% improvement in inspiratory capacity after exercise.7

NAC supplementation may also be useful in the management of type 2 diabetes. Oxidative stress, which can increase as a result of deficient intracellular glutathione, is known to reduce both cellular insulin sensitivity and beta-cell function. 

Enhanced beta-cell function may, in turn, increase the availability of cysteine.8 Insulin sensitivity in cells depleted of glutathione has been found to drop by nearly 40% from baseline values.9

Multiple studies have demonstrated positive effects for psychiatric conditions from long-term supplementation with NAC.10 Post-mortem studies have found that individuals with known psychiatric disorders have significantly low levels of intracellular glutathione in the prefrontal cortex.11

Safety, interactions, side effects

NAC has very few documented side effects. Mild gastric distress is the most commonly noted complaint, and this was reported in trials in which higher dosages were used. No interactions have been reported.

Cost, how supplied, dose

NAC is usually administered orally in powder-filled capsules. Multiple trials have verified the safety and tolerance of NAC doses as high as 6,900 mg/day.12 

Typical dose recommendations, however, are much more moderate, at 600 mg, 3 times daily. Considering the potential health benefit of NAC supplementation, its cost averages a reasonable $12 for a month’s supply. 

For those preferring to maintain adequate cysteine levels without supplementation, NAC is not found in food, but most high-protein foods, such as poultry, wheat, broccoli, and eggs, are good sources of cysteine.

Summary

NAC is a safe and readily available supplement that is critical in restoring and maintaining intracellular levels of the potent antioxidant glutathione. This supplement has the potential to play a broad and dynamic role in an individual’s overall health. 

For patients seeking a single supplement with multiple metabolic functions, NAC could be just the right fit.

Sherril Sego, FNP-C, DNP, is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

References


  1. Goepp J. The overlooked compound that saves lives. Life Extension Magazine. 2010. Available at lef.org/magazine/mag2010/may2010_N-Acetyl-Cysteine_01.htm

  2. Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr. 2004; 134(3):489-492. Available at jn.nutrition.org/content/134/3/489.long

  3. World Health Organization. WHO model list of essential medicines: 18th list. 2013. Available at apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf

  4. Van Shooten FJ, Besaratinia A, De Flora S, et al. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. 2002;11(2):167-175. Available at cebp.aacrjournals.org/content/11/2/167.long

  5. Franco R, Cidlowski JA. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ. 2009;16(10):1303-1314. Available at nature.com/cdd/journal/v16/n10/full/cdd2009107a.html

  6. Grey V, Mohammed SR, Smountas AA, et al. Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein. J Cyst Fibros. 2003;2(4):195-198. Available at http://www.cysticfibrosisjournal.com/article/S1569-1993(03)00097-3/abstract

  7. Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386. Available at journal.publications.chestnet.org/article.aspx?articleid=1089958

  8. Numazawa S, Sakaguchi H, Aoki R, et al. Regulation of the susceptibility to oxidative stress by cysteine availability in pancreatic beta-cells. Am J Physiol Cell Physiol. 2008;295(2):C468-C474. Available at ajpcell.physiology.org/content/295/2/C468.long

  9. Guarino MP, Afonso RA, Raimundo N, et al. Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action. Am J Physiol Gastrointest Liver Physiol. 2003;284(4):G588-G594.

  10. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011;36(2):78-86. Available at jpn.ca/vol36-issue2/36-2-78

  11. Gawryluk JW, Wang JF Andreazza AC, et al. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011;14(1): 123-130. 

  12. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007;7(4):355-359.


All electronic documents accessed September 2, 2014