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Nutrition With a Get-Big Mission: Got the NAC?

Oral forms of glutathione are useless because they degrade into the three amino acids that make up glutathione, essentially eliminating its potency. Supplementing cysteine would be more effective than using preformed glutathione; however, there are also problems with cysteine. It’s unstable and relatively insoluble, and it’s linked to kidney-stone formation when used in large doses.

N-acetylcysteine is a nutrient popular with both bodybuilders and life-extensionists. It’s considered an antioxidant and is added to many food supplements targeted to bodybuilders and athletes. Its primary advantage is that it acts as a substrate, or precursor, of the body’s synthesis of glutathione.

Glutathione is a tripeptide, which means that it consists of three bonded amino acids: cysteine, glycine and glutamate. Cysteine is the primary antioxidant and is thought to be responsible for much of the detoxifying effects associated with glutathione. Glutathione is a primary antioxidant and, along with vitamin C, is the most common water-soluble antioxidant in the body. While every cell in the body has glutathione, it’s particularly important for immune function and concentrates in the liver, where it aids in the liver detoxification process.

That latter effect makes glutathione of interest to athletes who use drugs that can accumulate in the liver and possibly lead to liver damage, such as oral anabolic steroids. Glutathione helps the liver make the drugs water-soluble so they can be excreted from the body. The liver uses glutathione to help detoxify other substances, such as pollutants, poisons and chemicals. Those with serious illness, such as AIDS or cancer, are typically depleted of glutathione.

Oral forms of glutathione are useless because they degrade into the three amino acids that make up glutathione, essentially eliminating its potency. Supplementing cysteine would be more effective than using preformed glutathione; however, there are also problems with cysteine. It’s unstable and relatively insoluble, and it’s linked to kidney-stone formation when used in large doses.

Other nutritional options for boosting glutathione include lipoic acid, whey protein (rich in cysteine) and NAC. Vitamin C helps recycle oxidized glutathione, another example of the synergy of antioxidant nutrients, while milk thistle, or silymarin, is particularly effective at increasing liver glutathione.

Of glutathione’s nutritional precursors, NAC has long been considered the most reliable in terms of both practical and cost-effective use. Perhaps the most common medical application of NAC is its ability to detoxify the common over-the-counter pain reliever acetaminophen, sold under the trade name Tylenol. Few people realize that acetaminophen is extremely toxic to the liver. Taking as few as 12 tablets at once can cause liver failure, and alcohol amplifies the effect. Acetaminophen causes liver toxicity because a metabolite of the drug is generated by the liver’s detoxifying system. Large amounts of glutathione are required to detoxify the metabolite, which means glutathione can be rapidly depleted. Supplying NAC leads to rapid synthesis of additional glutathione, thus preventing liver damage.

NAC is used to treat several other medical conditions, including AIDS, cystic fibrosis, chronic obstructive pulmonary disease and diabetes. One hypothesis suggests that cancer can be effectively treated by blocking glutathione synthesis in tumors, then using NAC to prevent oxidant damage to normal cells.1 A recent study found that providing cysteine alleviated oxidative stress and insulin resistance produced by a high sugar intake.2

Research has demonstrated that NAC has ergogenic effects if it’s taken prior to exercise and that it can help prevent excess muscle catabolism. An intriguing study found that NAC curbs gambling addiction, restoring levels of glutamate in the nucleus accumbens area of the brain.3 It may also be useful in treating methamphetamine—a.k.a. speed—addiction. One theory of aging suggests that loss of cysteine or thiol groups in body tissues leads to many of the negative health effects associated with the aging process, explaining why NAC is popular with the life-extension crowd. Cysteine is also the nutritional precursor of the amino acid taurine, which itself offers ergogenic benefits.

The biochemical pathways of NAC are well-known. Like many other orally taken substances, NAC undergoes extensive first-pass metabolism in the liver and kidneys, resulting in low concentrations of it in the blood. The NAC that escapes initial metabolism travels in the blood back to the liver, where it’s rapidly converted into cysteine, which in turn immediately converts into glutathione.

While the suggested supplemental dose of NAC is in the range of 600 to 1,200 milligrams daily, much larger doses are used therapeutically. Daily doses up to 8,000 milligrams are used without adverse effects, although a small percentage of people taking that much experience such side effects as nausea, vomiting and heartburn. As noted above, NAC is available as an over-the-counter supplement. Trouble is, spotty quality control during the manufacturing process can result in the premature oxidation of it.

Because of NAC’s natural sulfur content, the supplements tend to smell nasty, but that has no relationship to product potency, and it doesn’t mean that the supplement has degraded.

Much more serious were the results of a recent animal study.4 When mice were given NAC, they produced a red blood cell–derived substance that fooled their bodies into thinking they were low in oxygen. The substance, nitrosothiol, bypasses the normal oxygen-sensing systems in the lungs. That made the pulmonary arteries narrow to conserve oxygen, resulting in a localized increase in blood pressure in the lungs, known as primary pulmonary hypertension. Left untreated, PPH results in right-sided heart failure and death. It made the news several years ago when the diet drug combination known as fen-phen was linked to it.

In the study, the mice took NAC for three weeks. It was converted in their bodies into nitrosothiol and S-nitroso-acetylcysteine. The normal mice that got NAC developed PPH, but other mice in the study—mice that lacked an enzyme that produces nitric oxide from the amino acid arginine—didn’t convert the NAC and didn’t develop the disease.

Primary pulmonary hypertension is a serious disease, and symptoms such as fatigue, heavy breathing and fainting often don’t show up in the early stages. The question is, Is NAC safe for human use? Nearly all the negative side effects are linked to intravenous use, not oral intake. Also, studies show that when NAC is taken orally, it rapidly degrades in the liver and kidneys. In contrast, the rodents in the new study were continuously exposed to amounts of NAC that were 40 times higher than the dose shown to cause hypoxia, or lack of oxygen, in humans. Finally, countless studies have demonstrated that what’s toxic to rodents isn’t necessarily toxic to humans, and vice versa.

On the other hand, primary pulmonary hypertension is so serious that it would probably be prudent to avoid taking any more than 600 milligrams a day of NAC until human-based studies solidify the research. Ironically, NAC is used to treat conditions involving lung inflammation, such as cystic fibrosis, with good results. Since the doses used in those treatments are relatively massive in comparison to normal supplemental intake of NAC, you’d think that many cases of NAC-induced PPH would have shown up by now, but none have. Then again, it may be a slowly progressive disease that would take years to show up in humans.

In the meantime, you can effectively increase vital glutathione levels through other supplements, such as lipoic acid and whey protein, without any fears of future toxicity—or can you? More on that in future issues. IM



1 Yildiz, D. (2004). Inhibition of tumor growth by replacing glutathione with N-acetyl cysteine. Med Hypothes. 63:80-82.

2 Blouet, C., et al. (2007). Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance. Free Rad Biol Med. 42:1089-1097.

3 Grant, J.E., et al. (2007). N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: A pilot study. Biol Psychiatry. 62:652-657.

4 Palmer, L.A., et al. (2007). S-nitrosothiols signal hypoxia-mimetic vascular pathology. J Clin Invest. 117:2592-2601.

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