Home Glutathione Facts N-Acetylcysteine (NAC) cannot increase cellular Glutathione levels

N-Acetylcysteine (NAC) cannot increase cellular Glutathione levels

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Over the years, there have been countless papers written on the importance of glutathione (GSH) and the myriad of ways to supplement this free radical scavenger. By now, we are all aware of its significance in keeping us healthy, but, unfortunately, there are many myths on how to enhance cellular glutathione (GSH) effectively.

We have already discounted the most apparent strategy in one of our articles in which we discuss why taking glutathione itself will not increase its concentration inside the cell. So, let’s move on to the most often quoted myth that the amino acid cysteine is in limited supply in the body. We are aware that cysteine is one of the three building blocks that make up glutathione, but is there any evidence to suggest that we may be low on cysteine? And, regardless, would taking cysteine be effective in increasing cellular glutathione (GSH)? On initial observation, the principle behind the theory of cysteine deficiency being a cause of low glutathione (GSH) appears reasonably sound, but it is not that simple.

The first question is relatively easy to answer. The fact is that our diet usually contains plenty of cysteine and the other sulphur containing amino acid called methionine which can be easily converted into cysteine in the liver [1]. For example, the typical American diet supplies much more than the recommended required quantity of cysteine [2]. We can, therefore, rule out a cysteine deficiency. But would taking a cysteine supplement such as N-acetylcysteine (NAC) increase our cellular glutathione (GSH)? Unfortunately, it is not that easy, otherwise none of the chronic diseases attributed to low glutathione (GSH) would be so prevalent.

Cysteine, unlike most other amino acids, is extremely unstable and rapidly autoxidizes to cystine which is the oxidized disulphide form. It has exceedingly low solubility, and it will not be absorbed Cysteine, unlike most other amino acids, is extremely unstable and rapidly autoxidizes to cystine which is the oxidized disulphide form of cysteine. Cystine has exceedingly low solubility, and it will not be absorbed from the GI tract. Additionally, this cysteine autoxidation reaction, catalyzed by transition metal ions, generates oxygen free radicals and hydrogen peroxide. In high concentrations, this may result in cellular toxicity [3-6] and has the potential to be neurotoxic [7]. Our cells have adapted to this potential toxicity by storing cysteine in the form of glutathione (GSH) [8], which is far more stable to oxidation. We can therefore consider glutathione to be a safe storage for cysteine. It is important to note that consuming cysteine as part of our usual diet will never exceed the threshold to become toxic.

In summary, taking a cysteine supplement is of little use to increase glutathione (GSH) because our body tightly regulates both the storage and production of cysteine and any excess consumed is broken down into more stable byproducts. There is a notable exception which relates to acute glutathione (GSH) depletion due to acetaminophen (paracetamol) overdose as we shall see.

By far the most studied cysteine supplement is the cysteine prodrug N-Acetylcysteine (NAC). Several human clinical studies have determined the bioavailability of NAC. Orally delivered NAC undergoes extensive first-pass metabolism resulting in about 90% loss by enzymatic deacetylation to form cysteine in the small intestine [9]. As we have seen, this mainly gets converted to cystine and is of little use in healthy individuals or those suffering from a chronic undersupply of glutathione (GSH) due to aging or disease. Our notable exception is the observation in several studies that NAC is highly effective in elevating glutathione (GSH) under conditions where there has been a dramatic (acute depletion) drop in intracellular glutathione (GSH) levels, for instance as is the case in acetaminophen overdose. Here, the sharp decline in glutathione (GSH) levels, especially in the liver, to almost zero is effectively counteracted by NAC [10]. It immediately supplies available cysteine for repletion of glutathione and thus, recovery from toxicity. Unfortunately, this is where NAC has gained a false reputation as a go-to drug if low glutathione (GSH) is suspected. While immensely helpful indeed, it does not address our problem of supplementing glutathione (GSH) in cases of gradual depletion such as chronic illness or just simply getting older.

In contrast, diseases in which there is a prolonged and chronic decrease in glutathione (GSH) do not respond well to NAC treatment. An example of this is the situation that occurs in HIV/AIDS patients who experience a persistent drop in tissue glutathione (GSH) levels. In a clinical trial of AIDS patients were treated with 1.8 g/day of NAC for two weeks with the glutathione (GSH) status monitored in plasma and lymphocytes. During the treatment, no significant increase in glutathione (GSH) was observed [11]. Similar disappointing observations of HIV patients supplemented with NAC were also made by [12] and [13]. NAC has been tried in numerous chronic diseases with similarly disappointing results including cystic fibrosis protection against contrast-induced nephropathy and thrombosis [14].

The tight negative feedback control that glutathione (GSH) exerts on the first of two enzymes responsible for glutathione synthesis, GCL, can explain this phenomenon. This enzyme has the task of combining the amino acids glutamate and cysteine to form gamma-glutamylcysteine (GGC), which is used to produce glutathione (GSH) by the GS enzyme. As long as cellular glutathione is above a level considered to be adequate, which is called homeostasis, GCL is inhibited from making gamma-glutamylcysteine (GGC), no matter how much cysteine is available. However, when intracellular glutathione (GSH) is well below this homeostatic level, GCL is no longer inhibited and can actively utilize the cysteine supplied by NAC supplements. Several researchers have come to the same conclusion when trying to explain this fact [15]. Negative feedback controls exist as part of many of our body’s processes to tightly regulate certain functions, for example, our body temperature.

Supplementing with cysteine to increase cellular glutathione (GSH) is therefore of little use except in a few severe and limited cases mainly used in clinical settings.  The causes of glutathione (GSH) depletion in chronic diseases and how to effectively, rapidly and safely augment cellular glutathione (GSH) is now well understood.

Update

Why is NAC used so prevalently in clinical trials for treating diseases as diverse as Alzheimer’s disease, acute myocardial infarction, and type 2 diabetes [16]?  It appears that, overwhelmingly, most clinicians are well aware that glutathione depletion is a key factor in the progression of many diseases.  Medical textbooks are full of references on how to increase glutathione, however only in one very specific case: Acetaminophen overdose. NAC does work very well in this case and clinicians therefore assume that it generally works to increase glutathione.  Since NAC is cheap and has a relatively good safety profile, it has, paradoxically, become the “go to” drug for increasing glutathione.

This has led to a situation where more than 300 clinical trials using NAC are registered in the US trial database.  Yet, to this day, there is only one medically licenced use of NAC and that is acetaminophen overdose.  The medical literature is littered with unsuccessful clinical trials using NAC [16-22].   An excellent review article about the failures of NAC by Aitio [16] concluded that “Taking all the evidence together, it seems that in the clinical setting, NAC has so far not fulfilled the impressive promises that theory and experimental research have put forward.”

Even its only application as an antidote to acetaminophen overdose, NAC is not without problems.  Anywhere between 28 – 43% of people undergoing NAC treatment have an anaphylactoid (allergic) reaction [23].  This means they need to be given more drugs like antihistamines, corticosteroids, inhaled beta-agonists, and in severe cases intramuscular adrenaline to counteract the reaction. On the other hand, oral GGC supplementation has been shown to be effective at rapid replenishment of cellular glutathione and has been found to be free of side-effects.  

References

  1. Courtney-Martin, G., R.O. Ball, and P.B. Pencharz, Sulfur amino acid metabolism and requirements. Nutrition Reviews, 2012. 70(3): p. 170-175.
  2. Lang, C.A., The impact of glutathione on health and longevity. Journal of Anti Aging Medicine, 2001. 4(2): p. 137-144.
  3. Nath, K.A. and A.K. Salahudeen, Autoxidation of cysteine generates hydrogen peroxide: cytotoxicity and attenuation by pyruvate. American Journal of Physiology, 1993. 264(2): p. F306-F314.
  4. Harman, L.S., C. Mottley, and R.P. Mason, Free radical metabolites of L-cysteine oxidation. Journal of Biological Chemistry, 1984. 259(9): p. 5606-11.
  5. Viña, J., et al., The effect of cysteine oxidation on isolated hepatocytes. Biochem. J., 1983. 212(1): p. 39-44.
  6. Wang, X.F. and M.S. Cynader, Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity. The Journal of Neuroscience, 2001. 21(10): p. 3322-3331.
  7. Janáky, R., et al., Mechanisms of L-Cysteine Neurotoxicity. Neurochemical Research, 2000. 25(9): p. 1397-1405.
  8. Aoyama, K., M. Watabe, and T. Nakaki, Regulation of Neuronal Glutathione Synthesis. Journal of Pharmacological Sciences, 2008. 108(3): p. 227-238.
  9. Olsson, B., et al., Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. European Journal of Clinical Pharmacology, 1988. 34(1): p. 77-82.
  10. Yang, R.K., et al., Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity. Critical Care, 2009. 13(2).
  11. Witschi, A., et al., Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. AIDS Research & Human Retroviruses, 1995. 11(1): p. 141-3.
  12. Akerlund, B., et al., Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. European Journal of Clinical Pharmacology., 1996. 50(6): p. 457-61.
  13. Nakamura, H., H. Masutani, and J. Yodoi, Redox imbalance and its control in HIV infection. Antioxidants & Redox Signaling, 2002. 4(3): p. 455-64.
  14. Rushworth, G.F. and I.L. Megson, Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & Therapeutics, 2014. 141(2): p. 150-159.
  15. Nielsen, H.B., et al., N-acetylcysteine does not affect the lymphocyte proliferation and natural killer cell activity responses to exercise. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, 1998. 275(4): p. R1227-R1231.
  16. Aitio, M.-L., N-acetylcysteine – passe-partout or much ado about nothing? British Journal of Clinical Pharmacology, 2006. 61(1): p. 5-15.
  17. Tam, J., et al., Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev, 2013(7): p. Cd007168.
  18. Wang, G., et al., N-acetylcysteine in Cardiac Surgery: Do the Benefits Outweigh the Risks? A Meta-Analytic Reappraisal. Journal of cardiothoracic and vascular anesthesia, 2011. 25(2): p. 268-275.
  19. Sochman, J., N-Acetylcysteine Somewhere Between Scylla and Charybdis. J Am Coll Cardiol, 2010. 56(13): p. 1067-a-.
  20. Ashworth, A. and S.T. Webb, Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery? Interact CardioVasc Thorac Surg, 2010. 11(3): p. 303-308.
  21. Darmaun, D., et al., Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes, 2008. 9(6): p. 577-82.
  22. Ahola, T., et al., N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. The Journal of Pediatrics, 2003. 143(6): p. 713-719.
  23. Sandilands, E.A. and D.N. Bateman, Adverse reactions associated with acetylcysteine. Clinical Toxicology, 2009. 47(2): p. 81-88.

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