University of VA Health System - Some antioxidant supplements or mega-dose multivitamins taken to enhance athletic performance, prevent disease, or slow aging contain the anti-oxidant NAC that a new study suggests could be harmful in high-doses over a period of time. According to this research, N-acetylcysteine (NAC), an antioxidant commonly used in nutritional and bodybuilding supplements, can form a red blood cell-derived molecule that makes blood vessels think they are not getting enough oxygen. This could lead to pulmonary arterial hypertension (PAH), a serious condition characterized by high blood pressure in the arteries that carry blood to the lungs. The results appear in the September 2007 issue of the Journal of Clinical Investigation.

“NAC fools the body into thinking that it has an oxygen shortage,” said Dr. Ben Gaston, UVa Children’s Hospital pediatrician and researcher who led the study. “We found that a NAC product formed by red blood cells, know as a nitrosothiol, bypasses the normal regulation of oxygen sensing. It tells the arteries in the lung to ‘remodel’; they become narrow, increasing the blood pressure in the lungs and causing the right side of the heart to swell.”

Gaston notes that this is an entirely new understanding of the way oxygen is sensed by the body. The body responds to nitrosothiols, which are made when a decreased amount of oxygen is being carried by red blood cells; the response is not to the amount of oxygen dissolved in blood. He says that this pathway was designed much more elegantly than anyone had previously imagined. “We were really surprised”, he said.

The research team administered both NAC and nitrosothiols to mice for three weeks. The NAC was converted by red blood cells into the nitrosothiol, S-nitroso-N-acetylcysteine (SNOAC). The normal mice that received NAC and SNOAC developed PAH. Mice missing an enzyme known as endothelial nitric oxide synthase did not convert NAC to SNOAC, and were protected from the adverse effects of NAC, but not SNOAC. This suggests that NAC must be converted to SNOAC to cause PAH.

Could regular use of NAC produce the same effects in humans? The next step is to determine a threshold past which use of the antioxidant NAC becomes detrimental to heart or lung function, according to Dr. Lisa Palmer, co-researcher of the study.

“The more we understand about complexities in humans, the more we need to be aware of chemical reactions in the body,” said Palmer.

According to Gaston and Palmer, NAC is being tested in clinical trials for patients with cystic fibrosis as well as other conditions; and clinical trials with nitrosothiols are being planned. These results, Palmer says, should motivate researchers to check their patients taking NAC for PAH.

Editorial note - The full research article is available at the last link below. The mice who developed the lung problems in the study were given 10 mg per ml NAC in their drinking water. It is hard to translate this into any human dose equivalents, but if a person took in only 1 liter of such spiked water per day, that would be a 10,000 mg or 10 gram daily dose of NAC. Most over-the-counter nutritional supplements use around 650 mg as their dose, but doctors in emergency departments and ICU’s do use high-dose NAC to treat acetaminophen overdose with no known acute toxicity. A slight tendency toward problems, however, was seen even in mice drinking only 1 mg per ml NAC in drinking water. This study should serve as a caution for anyone choosing to supplement with very high doses of NAC.

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