|Part II N-Acetylcysteine (NAC): An Old Nutrient Attracts New Research.
by Richard A. Passwater, Ph. D.
In the previous issue, I discussed why AIDS researchers were excited about two nutrients, Vitamin C and N-acetylcysteine (NAC). While most Whole Foods readers know a great deal about the roles of vitamin C in nourishing the body, some readers may not be all that familiar with the roles of the sulfur-containing nutrients, such as NAC, in nourishing the body. Therefore, I promised to provide more background on NAC in this article. 
Our understanding of the many nutritional and biochemical roles of sulfur-containing nutrients is expanding rapidly at this time. We are learning more about how glutathione and its sulfur-containing precursors are important in keeping our bodies nourished, our immune systems healthy, and in protecting us against cancer and heart disease.
Glutathione, cysteine, methionine, selenocysteine and selenomethionine have been important in my research for over thirty years. Even before that, I believe that some of the health pioneers indirectly realized the importance of these compounds as a group, even though they didn't understand much about the roles of the individual compounds. When the "pioneers" spoke so favorably of getting adequate "sulfur" in the diet, I believe that they were really testifying to the importance of these sulfur-containing nutrients. Not much has been said about them in "mainstream" nutrition, but today, interest in learning how sulfur-containing nutrients nourish the body is increasing.
Researchers are rushing to study the roles of these nutrients in halting the dreaded Human Immunodeficiency Virus (HIV), breaking up lipoprotein(a) [Lp(a)], detoxifying harmful chemicals, scavaging free radicals and possibly protecting against some cancer processes. Since these nutrients are normally produced in plants, man and other animals, they have always been a part of the human diet.
Sulfur-containing nutrients play several critical roles in the body including detoxification and protecting cells and cellular components against oxidative stress. My interest in glutathione and cysteine began in the 1960's when they were found to be protective against nuclear radiation. I reasoned that the same mechanism of action would make them excellent free-radical scavengers as well. They did, and twenty-one years ago I reported that, "sulfhydryl compounds that are excellent radiation protectors are also free-radical scavengers, peroxide decomposers, catalysts of sulfhydryl-disulfide exchange, and possibly can implement repair of damaged sites. Sulfhydryl compounds and vitamin E also increase the body's tolerance to selenium." 
Today, NAC is of greater interest than glutathione itself. NAC is produced in living organisms from the amino acid cysteine. Thus, NAC is a natural sulfur-containing amino acid derivative found naturally in foods and is a powerful antioxidant. [3,4] These dual properties help repair oxidative damage in the body.
Both NAC and glutathione are well absorbed. [5-8] NAC is rapidly metabolized, and only about ten percent of the amount consumed stays in the blood for an appreciable time.  Much of the NAC is very rapidly consumed in producing intracellular glutathione. However, even the thiol metabolites of NAC are good antioxidants.
NAC readily crosses cell membranes, even in HIV-infected cells, whereas glutathione does not enter into HIV-infected cells in adequate amounts. [10-12] Even so, NAC does not seem to raise tissue or blood levels of glutathione above the desired ranges.  Thus, the nutrient role of NAC is to help maintain healthy levels of intracellular glutathione, especially whenever a condition has limited glutathione production. This nutrient role of maintaining optimal levels of essential body compounds is different from "drug roles" in which body compounds are just elevated without homeostasis or normal body regulation.
Since NAC is a powerful antioxidant nutrient, it has been of special interest to athletes for some time as heavy exercise increases oxidative damage in the body. [13-15] But the latest research interests are in AIDS and heart disease.
A growing area of interest is that research has pinpointed a specific lipoprotein called Lp(a) as one of the two most reliable indicators of heart disease risk. [16-20] The other reliable indicator is the level of vitamin E in the blood.  Lp(a) is a much more reliable indicator than blood cholesterol level, low density lipoprotein, high-density lipoprotein or their ratios to each other.
Diets and drugs designed to lower blood cholesterol levels do not lower Lp(a) levels. Now recent research has found that NAC is the most effective nutrient known to lower Lp(a) levels. NAC reduces Lp(a) by almost 70%. [22-25] Lp(a) consists of a LDL particle attached to the large glycoprotein apo(a) by one or more disulfide bonds. NAC breaks up the disulfide bonds by converting each disulfide group into two sulfhydryl groups now in two separate compounds.
NAC also inhibits heart damage by preventing LDL from being oxidized and by destroying free radicals produced after an infarction. [26-29]
Immunity and AIDS
NAC affects immunity via its role in intracellular glutathione production. This role becomes critical when normal glutathione production pathways are impaired, as for example, by the Human Immunodeficiency Virus (HIV). Eck has shown that reduced intracellular glutathione is the "direct and early consequence of retroviral infection." 
Intracellular glutathione has a powerful influence on how well T- and B-lymphocyte cells function. [12,30] In addition, intracellular glutathione availability affects the production of phagocytes (macrophages, monocytes and neutrophils). T-cells and B-cells are lymphocytes (white cells that are the principal cells of lymph). B-cells produce antibodies and are responsible for humoral response, while T-cells help produce antibodies, secrete interferon and other lymphokines, and are responsible for cell-mediated response. The phagocytes have the function of killing viruses, bacteria and fungi.
Free radicals can impair the immune system and NAC can protect against free radicals and enhance the immune system. [31-33]
As discussed in detail in the previous issue, NAC has been shown to block the AIDS virus (HIV) production in vitro, apparently by increasing glutathione levels in HIV-infected cells. [34-46] In the previous article, I also discussed the synergism of NAC and vitamin C. Beside vitamin C reducing oxidized glutathione back to free reduced (active) glutathione, vitamin C and NAC had complementary actions to slow the replication of the AIDS virus.
I reported last month that in addition to NAC and vitamin C (especially Ester-C (tm)), AIDS Related Complex (ARC) and AIDS patients should be sure that they are well-nourished with cysteine, selenium, garlic, vitamin B-12, folic acid, zinc and Dimethylglycine (DMG). Add Coenzyme Q-10 to this list. Dr. Karl Folkers and colleagues at the Institute for Biomedical Research at the University of Texas have expanded on their recent study of ARC patients who have now lived for over four years with ARC without developing "full-blown" AIDS by taking 200 milligrams of Coenzyme Q-10 daily. Their first small-scale study was published in Biochemical and Biophysical Research, and their expanded study will be published in the Journal of Applied Nutrition. 
These sulfur-containing nutrients are also gaining new interest because they protect against toxins. NAC is particularly effective and NAC detoxifies several toxic agents including the heavy metals such as mercury, lead and cadmium [48-54], drugs including acetaminophen (e. g. Tylenol (tm)) [9,55-61], herbicides such as paraquat , environmental pollutants such as carbon tetrachloride and urethane [63-67], and microorganism including aflatoxin and Escherichia coli [68-70].
NAC, cysteine and glutathione contain sulfur in the form of sulfhydryl groups. Sulfhydryl groups directly react with many poisons, especially heavy metals such as lead, mercury and cadmium. These sulfur-containing nutrients are the bodies first line of defense against many poisons as they tie-up the poisons right in the gut. They also offer second-line and third-line defenses in the liver and various individual cells. Sulfhydryl groups also help remove toxins indirectly via an enzyme system called the P-450 System.
NAC also has a secondary role in detoxification since it helps produce optimal amounts of glutathione which also conjugates with most "foreign" compounds and excess oxidizers that enter cells. The harmful compounds that have been conjugated with glutathione then pass harmlessly out of the body through the biliary system. 
Although NAC is a food component and a nutrient accessory factor, it is also marketed as a drug with approved medical claims. Other nutrients also have dual classifications, but just because a nutrient is also approved for "drug" usage, its role as a nutrient is not affected unless drug claims are made. If the nutrient is used to nourish the body, it remains a nutrient. If the nutrient is used to treat a non-deficiency disease, then this use changes its legal classification to a drug.
NAC is approved as a drug for use to prevent liver damage from acetaminophen overdose. Either NAC tablets or solutions may be used to protect against acetaminophen overdose. Normally, the 20 percent solution is mixed with a cola drink.
The Lancet reports that NAC is also effective in reducing the toxic effects of carbon tetrachloride, chloroform and carbon monoxide.  NAC can also reduce the side effects of drugs such as doxorubicin, ifosphamide, valproic acid and alcohol. [9,60,61]
NAC protects against cancer by both of its roles as antioxidant and detoxifier. [4,70-76]
NAC also reduces the toxic effects of some chemotherapy agents such as cisplatin and oxazophosporine-based agents. [77,78]
NAC has been used for about thirty years to break up mucus in persons having bronchopulmonary diseases including chronic bronchitis, cystic fibrosis, asthma, sinusitis and pneumonia.  NAC helps reduce the viscosity of mucus so that it may be more easily coughed up.  NAC accomplishes this by converting the disulfide bonds of the mucoproteins into sulfhydryl bonds and cleaving the mucoproteins into smaller molecules.
Several companies provide a 10 or 20 percent NAC solution as a nebulizer spray (such as Bristol Laboratories' Mucomyst TM), while others such as Italy's Zambon group provides NAC in tablet form. When a nutrient is topically applied or sprayed into the lungs, it can then be classified also as a drug because it does not then enter into metabolism to nourish the body when it is administered in this way. (However, this is different from having a nutrient absorbed into the body by sublingual or nasal membrane application which allows the nutrient to nourish the body.)
Optimal Intake Ranges
There are a few toxicological studies of NAC available and the following observations can be made. NAC in normal food supplementation ranges is without known toxicity and has been administered by physicians under supervision in doses of 500 milligrams to four grams daily. Daily levels of 1,000 milligrams of NAC per kilogram in rats for several months did not produce adverse effects in behavior, weight gain, hematology, liver function and kidney function.  (That's the equivalent of 60 grams of NAC per day for a 132 pound person, 80 grams per day for a 176 pound person, or 100 grams per day for a 220 pound person.)
When administered via nebulizer, adverse effects can include stomatitis, nausea and nasal irritation.  Intravenous administration could also produce edema and a rapid heart beat. 
Larger quantities used for treating acetaminophen overdoses have produced adverse reactions such as nausea, vomiting, and other gastrointestinal symptoms.  Rash, with or without mild fever, has been reported on rare occasions with very large quantities. Intravenous administration of more than 150 milligrams of NAC per kilogram of body weight within a fifteen minute period may produce toxic or other undesirable effects. 
The mouse LD50 of oral NAC is reported to be about 8,000 milligrams of NAC per kilogram in the mouse, and 5050 milligrams per kilogram in the rat. [81,82] For more details on NAC safety, please refer to references 83 through 88.
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