NAC – A New Daily Essential?
Fresh Insights on How This Molecule Works
N-acetylcysteine (NAC) is used to support the health of the liver, lungs, circulation, immune system, and more. Recent studies exploring the chemistry of NAC more thoroughly illustrate that NAC has three main molecular mechanisms which interact with each other in a variety of ways. These mechanisms include direct and indirect antioxidant activity, di-sulfide bond breaking activity, and homeostatic influence on glutamatergic and dopaminergic pathways.
STRUCTURE AND METABOLISM OF NAC
As its name suggests, NAC is a derivative of the amino acid cysteine. The only difference between the two compounds is that NAC has an acetyl group (-CH3O) bound to the nitrogen on cysteine. Both compounds also contain a free thiol group (-SH).
Cysteine is considered a semi-essential amino acid. As long as other amino acids are in good supply (especially methionine and serine), cysteine can be synthesized in the body. Eating adequate protein usually provides sufficient levels of cysteine under normal physiological conditions, but there are some situations where supplementing with NAC appears to provide additional benefit.
NAC has indirect (yet potent!) antioxidant activity, by providing a biological source of cysteine for glutathione synthesis. NAC’s role in regenerating glutathione, the “master antioxidant,” positions it as a key player in optimizing cellular function and overall health.
Orally administered NAC undergoes first-pass metabolism in the liver and kidneys, which frees the cysteine, making it available for the synthesis of glutathione. Glutathione (also known as GSH) is a tripeptide synthesized from glutamine, glycine and cysteine. The rate-limiting step in GSH synthesis requires cysteine as a substrate and its ready availability is critical to the process. Glutathione is the body’s main intracellular antioxidant, needed for the stability and integrity of all cellular functions. GSH has direct antioxidant effects but also acts as a substrate for numerous antioxidant enzymes as well.
THE IMPORTANCE OF ADEQUATE GLUTATHIONE
Because glutathione is a reducing agent that combats free radicals and protects cells from oxidative damage, depletion puts cellular health at risk and compounds or increases the chances of countless health problems.
We know that glutathione is dangerously depleted by both acute and chronic illness. Physicians dealing with chronic illness have observed that glutathione deficiency is found in nearly all very ill patients. This is true for people of all ages. Low glutathione or glutathione deficiency is correlated with many conditions, including smoking, alcoholism, asthma, cognitive-behavioral problems, diabetes, metabolic syndrome, and neurodegenerative disorders.
Researchers are beginning to understand why low GSH/GSH deficiency correlated conditions become chronic and do not resolve despite diligent medical intervention. As GSH is depleted, the increasing oxidative stress associated with disease may actually disable the switch called Nrf2 that turns on the enzymes that make glutathione. Thus, Nrf2 “burnout” may decrease glutathione formation, leaving the tissues deficient in the glutathione they need for proper cellular function.
While research continues on the role of glutathione deficiency in the pathophysiology of various disorders, it is now clear that GSH depletion is relevant whenever there has been severe or prolonged oxidative stress, and methods for repleting and maintaining glutathione should play an increasingly important role in health management. NAC appears to support the synthesis of glutathione (GSH) under conditions when the demand for GSH is increased, during oxidative stress.
MECHANISMS OF NAC
NAC REPLENISHES GLUTATHIONE
As an FDA approved drug, intravenous NAC is the treatment of choice for acetaminophen overdose because it replenishes glutathione in the liver. Glutathione clears the toxic metabolite of acetaminophen, which would otherwise damage liver cells and trigger an immune response.
Animal and human studies suggest that oral NAC administration also increases GSH levels in numerous body tissues, in both red and white blood cells, in plasma and in lung fluids. While glutathione synthesis depends on adequate available cysteine, glutamine, and glycine, cysteine is the rate-limiting substance for the reaction and arguably the most influential on glutathione status.
NAC HAS DIRECT ANTIOXIDANT ACTIVITY
As if replenishing one of the body’s most important antioxidants weren’t enough, NAC also has direct antioxidant action. Its free thiol group can interact with electrons to directly neutralize reactive oxygen species. There are two categories of oxidative species that NAC can potentially neutralize: hypochlorous acid and related compounds (HOX) and nitrogen oxide (NO2).
HOX compounds are produced by activated neutrophils and monocytes through the activity of myeloperoxidase (MPO) and play a role in the immune response. NO2 is a major component of indoor and outdoor air pollution (from motor vehicles, cigarette smoke, burning fuel, and other sources) and is involved in epithelial injury to the lungs. In vitro and in vivo studies suggest biological plausibility for inhaled NAC to neutralize HOX and NO2 in lung tissue.
NAC BREAKS DISULFIDE BONDS
Meanwhile, a second mechanism of action allows NAC to work as a mucolytic.
NAC is a reducing agent of protein disulfide bonds through a reaction called the thiol-disulfide interchange. Mucus gels in the respiratory tract are highly cross-linked by disulfide bonds (S-S). NAC breaks the bonds and adds hydrogens, thus splitting the molecule in two. This reaction is called a thiol-disulfide interchange.
In comparison with cysteine and glutathione, NAC has the greatest ability to break disulfide bonds in proteins. This ability explains its mucolytic activity, but the effects likely extend beyond that.
Recent evidence shows this mechanism releases free thiols, which have better antioxidant activity than NAC and can also boost the synthesis of GSH and other reduced proteins. One of these reduced proteins is mercaptoalbumin, which has an important direct antioxidant activity.
Research has also shown that NAC has similar activity against fibrin formation, an insoluble protein formed from fibrinogen during the clotting of blood. NAC’s application in supporting healthy circulation and hemostasis is currently under investigation.
NAC SUPPORTS GLUTAMATE HOMEOSTASIS
A third potential mechanism of NAC, is in the early stages of investigation. NAC has shown positive clinical effects for a variety of neurological and cognitive-behavioral concerns and is currently in use adjunctive integrative support for mental health. The theory is that NAC can convert into l-cystine, which interacts with a cell membrane transporter called the cystine-glutamate antiporter. This transporter moves l-cystine into the cell and carries l-glutamate out. Glutamate in the extracellular space then modulates glutamate release from neurons, including in the brain.
CLINICAL RELEVANCE OF NAC
The biochemical abilities of NAC to support antioxidant defenses, break disulfide bonds, and modulate brain glutamate levels mean that this single molecule could potentially affect nearly every aspect of physiology and health.
Aside from NAC’s support of overall cellular health through antioxidant regeneration, NAC’s additional mechanisms of action can be applied to supporting five key physiological systems of health.
LIVER HEALTH
If prescription NAC can reduce liver damage from acetaminophen overdose, can dietary NAC play a role in other types of toxic exposure? After all, the liver is a central processing depot for all toxins that pass through the body and depends on an adequate supply of nutrients for optimal function.
Glutathione is one of several substances in the liver that acts in phase II to conjugate toxic metabolites. It’s especially important for conjugating xenobiotics, such as chemicals in plastics and personal care products. Because of its role in regenerating glutathione, oral NAC is commonly used to support everyday detoxification pathways.
IMMUNE HEALTH
NAC’s role in regenerating glutathione makes it important for immune health. Studies conducted in humans show that NAC can support the production of natural killer (NK) cells, which are major players in the innate immune response.
A randomized, controlled trial found that supplementing with 600 mg of NAC twice a day for six months supported cell-mediated immunity and wellness through the winter months. Another study showed that NAC supported a healthy inflammatory response to seasonally acquired health issues.
RESPIRATORY HEALTH
Mucus in the nose, throat, sinuses, and lungs serves an important purpose. It protects the lining of the respiratory tract and acts as a barrier to the entry of foreign particles. However, when mucus becomes thick and viscous, it can be problematic. As mentioned earlier, NAC addresses this issue by breaking the disulfide bonds within mucus gels and thinning the mucus.
In addition, as previously stated, NAC provides a rich source of cysteine to replenish endogenous glutathione stores. This is particularly relevant to lung health because GSH is one of the few antioxidants that’s expressed in higher levels in lung epithelial lining fluids than in plasma.
CIRCULATORY HEALTH
NAC’s ability to break disulfide bonds extends beyond respiratory mucus. This mechanism may also support healthy hemostasis and blood circulation.
An in vitro study of plasma from healthy human subjects found that NAC modulated levels of several coagulation factors. And a study published in the prestigious journal Circulation confirmed with a mouse model that NAC is a potent mediator of coagulation and circulatory health. Small studies in humans have been consistent with these findings.
NEUROLOGICAL AND MENTAL HEALTH
NAC’s ability to influence glutamate levels in the brain opens up the possibility that the molecule may be useful to support mental health. NAC has shown promise for supporting both dopamine and glutamate regulation. Additional mechanisms that may influence mental and emotional health include effects on inflammatory pathways. Other studies suggest that it may support healthy behavior and mood. The promising evidence from these early studies needs to be confirmed over time.
PRACTICAL USE OF NAC
NAC is a naturally occurring substance that has been shown to support antioxidant defenses and numerous aspects of health. Studies suggest that NAC has a good safety profile with a low risk of adverse effects. It may interact with some medications, so always check for potential risks.
NAC as an FDA approved drug is administered orally, intravenously, or via inhalation in a variety of medical situations. As a dietary supplement, studies suggest taking 200 to 600 mg of NAC orally, twice a day. It can be considered for either temporary support or for long-term health optimization.
As more patients and practitioners shift their focus away from disease management and toward health optimization, it becomes imperative to consider the very basics of cellular health. Our cells are the fundamental units of life. When we support cell function, the benefits potentially extend to all areas of wellness.