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The Many Hats of NAC

Recent research is pointing to new uses for N-acetyl-cysteine.

By Jacob Schor, ND

What happened to the good old days when you could grab a bottle of vitamins off the shelf and tell a patient, "These are good for you"? Now it seems the more we know, the more difficult it is to find something we can support as a panacea: something good for all people all of the time.

Rather, we are starting to understand that many supplements have their value in a particular time and situation, and should be avoided at other times and in other people. These thoughts are prompted by the current excitement regarding N-acetyl-cysteine (NAC).

NAC is one of the most effective ways to fill the body with cysteine, and in doing so, to increase glutathione production. Glutathione is the body's mainstay chemical for quenching or putting out reactive oxygen species (ROS), those hot little radicals that can create a cascade of oxidative damage within the cell. This makes NAC sound like a good thing and for years we've put it to good use. For years, we've employed it in cystic fibrosis, as a mucolyltic decongestant, suppressing cold symptoms as well as for environmental detoxification.

Recent research is pointing to new uses for NAC. It can and should be considered in a growing range of situations in which there is oxidant overload, including head trauma,1 pancreatitis,2 lung damage from inhaling paint thinner fumes,3 jaundice,4 sepsis,5 obesity,6 obsessive compulsive disorder,7 and so on. Now that acetaminophen poisoning is recognized as the number one cause of liver failure8 in the U.S., NAC's old role in treating overdoses and preventing liver damage shouldn't be forgotten. This stuff is cool.

Well, it's cool at least some of the time. When it comes to cancer treatment, NAC is an entirely different story. Lots of the stuff we like to use in treating cancer works by increasing ROS in cancer cells. Not just the nasty stuff that MDs use, like radiation treatment and chemotherapy, but many of the supplements we naturopaths adore. A partial list of ROS generators includes vitamin C,9 selenium,10 melatonin,11,12 curcumin,13 feverfew,14 ellagic acid,15 vitamin D,16 salvia17 and vitamin K3.18

Remember that NAC increases glutathione. Glutathione cancels out the ROS effect. Current understanding is that at least several of our anti-tumor substances work directly by depleting glutathione. Glutathione depletion inhibits or kills cancer cells. Decent evidence points to drug-induced glutathione depletion as a potential treatment strategy in prostate,19 pancreatic,20 melanoma21 and colon cancer.22 Common natural glutathione depleters we naturopaths use in cancer treatment include vitamin K3,23 salvia24,25 and l-glutamine.26 It isn't surprising to read in the literature that co-administration of NAC negates the anti-cancer effect of vitamin K3,27 feverfew,28 salvia,29 and vitamin D3.30

Looking at the other supplements which kill cancer cells by generating ROS; we should suspect that NAC will stop them from working as well. This is a troubling thought when you consider there are patients who take NAC for months, if not years, on end.

As much as NAC is a neat supplement, at this point, I am careful who I give it to and rarely ever use it with cancer patients. If we are going to use NAC, does it make sense to use supplements that act by generating ROS? In a black and white world where things are either reactive oxygen species or glutathione inducers, we probably shouldn't mix the two categories. In the real world, who knows? Real life tends to be more complicated than they told us in medical school.

Nature tends to do things in cycles, swinging a pendulum from one homeostatic extreme to another. Could it be that over the normal course of events, a cell swings back and forth between two oxidative extremes, first leaning towards higher levels of ROS and then swinging to increased glutathione effect and lower levels of oxidative activity? It would make sense. High levels of glutathione activity are protective against genetic mutation and cancer initiation while the alternating period of increased ROS might destroy any cancerous cells that might have developed. I haven't chanced on anything in the literature to support this idea, but it isn't a stretch of the imagination to think it might be true. In patients who take NAC for long periods of time, would it make sense to call time out occasionally and have them take supplements that stimulate the production of ROS during the interlude?

In the good old days, naturopaths could simply stimulate the vital force and rely on nature to sort things out. Today, as we immerse ourselves in this new world of complex interventional biochemistry, we can still model our protocols so they mirror the natural processes invoked by the vital force, or at least we can try to. Once we step beyond the simple elements of our tradition, seemingly simple interventional therapies force the practitioner to make decisions we wish might be better left to the vital force. Even something as simple and as useful as NAC opens up a Pandora's Box.

References

  1. Hicdonmez T, et al: Neuroprotective Effects of N-acetylcysteine on Experimental Closed Head Trauma in Rats. Neurochem Res. 2006 May 9; [Epub ahead of print].
  2. Yagci G, et al: Beneficial effects of N-acetylcysteine on sodium taurocholate-induced pancreatitis in rats. J Gastroenterol. 2004;39(3):268-76.
  3. Dillioglugil MO et al: Protective effects of N-acetylcysteine on the peroxidative changes of rat lungs exposed to inhalation of thinners. Respirology. 2005 Nov;10(5):615-9.
  4. Akca T et al: The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage. J Surg Res. 2005 Nov;129(1):38-45.
  5. Ozdulger A et al: The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock. 2003 Apr;19(4):366-72.
  6. Kim JR et al: Association of anti-obesity activity of N-acetylcysteine with metallothionein-II down-regulation. Exp Mol Med. 2006 Apr 30;38(2):162-72.
  7. Lafleur DL, et al: N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006 Jan;184(2):254-6. Epub 2005 Dec 22.
  8. Perkins JD. Acetaminophen sets records in the United States: number 1 analgesic and number 1 cause of acute liver failure. Liver Transpl. 2006 Apr;12(4):682-3.
  9. Zheng QS et al: Ascorbic acid induces redifferentiation and growth inhibition in human hepatoma cells by increasing endogenous hydrogen peroxide. Pharmazie. 2002 Nov;57(11):753-7.
  10. Zhao R et al: Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells. Cancer Res. 2006 Feb 15;66(4):2296-304.
  11. Buyukavci M et al: Melatonin cytotoxicity in human leukemia cells: relation with its pro-oxidant effect. Fundam Clin Pharmacol. 2006 Feb;20(1):73-9).
  12. Medina-Navarro R et al: Pro-oxidating properties of melatonin in the in vitro interaction with the singlet oxygen. Endocr Res. 1999 Aug-Nov;25(3-4):263-80.
  13. Moussavi M et al: Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis. 2006 Feb 25.
  14. Guzman ML et al: The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005 Jun 1;105(11):4163-9. Epub 2005 Feb 1.
  15. Bhosle SM et al: Enhancement of radiation-induced oxidative stress and cytotoxicity in tumor cells by ellagic acid. Clin Chim Acta. 2005 Sep;359(1-2):89-100.
  16. Ravid A and Koren R: The role of reactive oxygen species in the anticancer activity of vitamin D. Recent Results Cancer Res. 2003;164:357-67.
  17. Liu J et al: Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells. Life Sci 2001 Sep 7;69(16):1833-50.
  18. Lin C et al: Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation. Pharmazie. 2005 Oct;60(10):765-71.
  19. Coffey RN et al: Thiol-mediated apoptosis in prostate carcinoma cells. Cancer 2000 May 1;88(9):2092-104.
  20. Schnelldorfer T et al: Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells. Cancer 2000 Oct 1:89(7):1440-7.
  21. Pendyala L et al: Effect of glutathione depletion on the cytotoxicity of cisplatin and iproplatin in a human melanoma cell line. Cancer Chemother Pharmacol 1997;40(1):38-44.
  22. Moussavi M et al: Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis. 2006 Feb 25; [Epub ahead of print].
  23. McAmis WC, Schaeffer RC Jr, Baynes JW, Wolf MB: Menadione causes endothelial barrier failure by a direct effect on intracellular thiols, independent of reactive oxidant production. Biochim Biophys Acta. 2003 Jun 17;1641(1):43-53.
  24. Liu J et al: Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells. Life Sci 2001 Sep 7;69(16):1833-50.
  25. Liu J, Shen HM, Ong CN.Salvia miltiorrhiza inhibits cell growth and induces apoptosis in human hepatoma HepG(2) cells. Cancer Lett. 2000 May 29;153(1-2):85-93.
  26. Benlloch M et al: Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. J Biol Chem. 2006 Jan 6;281(1):69-79. Epub 2005 Nov 1.
  27. Nishikawa Y et al: Growth inhibition of hepatoma cells induced by vitamin K and its analogs. J Biol Chem. 1995 Nov 24;270(47):28304-10.
  28. Zhang S, Ong CN, Shen HM. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004 May 28;208(2):143-53.
  29. Liu J et al: Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells. Life Sci 2001 Sep 7;69(16):1833-50.
  30. Zhang S et al: Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 2004 May 28;208(2):143-53).

About the Author: Dr. Jacob Schor graduated with a bachelor of science degree from Cornell University and received his naturopathic training at National College of Naturopathic Medicine. He currently practices at the Denver Naturopathic Clinic. E-mail Dr. Schor at DrJacobSchor1@msn.com.



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Date Last Modified - Friday, 17-Oct-2008 12:10:25 PDT