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The benefits of NAC to human health

N-acetylcysteine (NAC) is a supplement form of the non-essential amino acid, cysteine and is associated with antioxidant capability, immune support, detoxification and much more. NAC has received a lot of positive attention recently, particularly in light of the pandemic and vaccination roll out, and in this week's blog we explore some of the evidence in relation to this and also its wider application. Cysteine is found in most high-protein foods, such as poultry, eggs, dairy, seeds, and legumes. Additionally, cruciferous vegetables such as cabbage, Brussels sprouts, broccoli, and kale, are rich sources of sulphur-containing compounds important in the production of cysteine.

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NAC was introduced in the 1960s as a mucolytic drug for chronic respiratory diseases to loosen thick mucus in the lungs and is used in hospital settings in patients with acute bronchopulmonary disease (pneumonia, bronchitis). It is also used to treat paracetamol toxicity. While oral cysteine does not make it through the digestive tract, supplemental cysteine in the form of NAC is effective at raising blood and tissue levels. The N-acetyl group attached to cysteine aids its absorption and also protects from stomach acid.

Precursor to Glutathione 1-3

One of the most important biological functions attributed to NAC, and its prime value, is its ability to boost the production of the most powerful antioxidant in the human body - glutathione. Glutathione is a tripeptide made from three amino acids: cysteine, glutamate, and glycine. Our cysteine levels therefore determine how much and how fast we make glutathione. Glutathione is known as the 'master antioxidant' because of its dominance throughout the body and its capacity to support and regenerate other antioxidants. As an antioxidant, glutathione helps to combat free radicals, which are molecules that can damage body cells and tissues at molecular level. It also plays a significant role in detoxification and reducing inflammation. Its vital roles include:

boosting the immune system

detoxification of both xenobiotic and endogenous compounds

cofactor for several antioxidant enzymes

regeneration of vitamins C and E

neutralization of free radicals

regulation of cellular proliferation and apoptosis

support for mitochondrial function and maintenance of mitochondrial DNA.

So why are so many of us depleted? - Common threats to glutathione levels include ageing, medications, poor nutrition, toxins, sedentary lifestyle, infections, and stress. With approximately half of the population in England now taking medications regularly, many of us relying on processed foods, and heightened levels of chronic stress, it is no wonder that so many of us are in poor health. In fact, the depletion of glutathione has been associated with a range of illnesses and chronic diseases including neurodegenerative, pulmonary, liver, immune, and cardiovascular disease. Furthermore, its antioxidant capabilities have been shown to protect DNA, cells, tissues, and organs from damage, inflammation, and toxins. The significant role of sufficient glutathione to health has therefore become ever more evident.

Mechanism of Action in Immune Function 1-6

Perhaps of particular concern at the moment is the many ways in which NAC can boost immune function. These include:

Increasing glutathione concentrations in the blood

Having its own antioxidative properties to protect against cellular damage

Breaking disulphide bridges between macromolecules, disrupting platelet aggregation and breaking bonds between blood cells and clotting factor, maintaining fluidity of blood and oxygen flow

Contributing to a reduction in mucus viscosity

Exhibiting vasodilatory properties by increasing cyclic GMP levels and by contributing to the regeneration of endothelial-derived relaxing factor (a potent vasodilator)

Reducing the formation of proinflammatory cytokines, such as IL-9 and TNF-α

Restoring Natural Killer cells

Thinning mucus in the bronchial tubes and boosting glutathione levels - helping to decrease the severity and frequency of wheezing, coughing and respiratory attacks

COVID-19 and other Viral Infections 1-15

The anti-inflammatory effects of glutathione in viral infection are employed through:

the decrease of reactive oxygen species (ROS) production

reduction of NF-kB activation

inhibition of ACE activity

ROS - Perhaps of most importance is NAC's ability to combat oxidative stress in the body. Oxidative stress is a nonspecific pathological condition reflecting an imbalance between the increased production of ROS and an inability of biological systems to detoxify the reactive intermediates or to repair the resulting damage.

Mounting evidence supports the concept that oxidative stress and associated inflammation contribute to the pathogenesis of various chronic diseases, which are now known to increase the risk of severe illness in COVID-19 patients.

Cellular immunity is necessary to fight viral infections and is regulated by an oxidant/antioxidant balance. In the immune cells of immune-compromised people, or the elderly, ROS is often increased due to decreased glutathione levels, which causes dysregulation of immune responses, particularly of T cell-mediated functions. This may explain the depressed cell-mediated immunity and increased mortality found in elderly persons as a result of infectious diseases, such as pneumonia.

Decreased levels of glutathione occurring in COVID-19 patients with chronic diseases could therefore be an initiating factor that moves redox homeostasis toward oxidative stress, and in doing so, exacerbates lung inflammation, leading to acute respiratory distress syndrome (ARDS), organ failure, and even death.

As ROS play a crucial role in inflammatory responses and viral replication, antioxidants such as NAC, that exert antiviral and anti-inflammatory effects, are suggested as candidates for the treatment of a cytokine storm induced by severe influenza.

Cytokine Storm - when we encounter an antigen, our body launches various immune responses, one of which is the release of proteins called cytokines. Cytokines communicate with the immune system and are key to controlling the growth and activity of other immune system cells. They therefore help and direct the body's immune and inflammation responses.

Cytokine responses are, however, elevated more so than normal in some COVID-19 patients, inducing an exaggerated and inappropriate immune response, and thus too much inflammation. This 'cytokine storm' can cause damage to organs, particularly the lungs. The immune system can therefore be more damaging in this respect than the virus itself.

The oxidative stress environment created by a cytokine storm may be attenuated by NAC's antioxidant effect. For example, NAC inhibited both H5N1 replication and H5N1-induced production of pro-inflammatory molecules (e.g., IL6, CCL5, CXCL8, and CXCL10) in lung epithelial cells.

Glutathione has also been shown to improve the life span of T-cells (white blood cells) which is crucial as they can become worn out and die because of a cytokine storm. Furthermore, NAC can help to mediate inflammatory pathways, lessening the damaging effects on the body.

NF-κB pathway support - RNA viruses need active NF-κB pathway support within host cells to replicate. For human coronaviruses, suppression of NF-κB significantly reduced the replication rate. NAC has demonstrated to inhibit NF-κB, as well as the replication of human influenza viruses in human lung epithelial cells. In theory therefore, NAC has the potential to inhibit SARS-Cov-2 because of its ability to negatively regulate NF-κB.

ACE Activity - The inflammatory response can be traced back to the pathway of viral entry through its receptor, angiotensin-converting enzyme 2 (ACE2). ACE2 is a protease that, with its companion the angiotensin-converting enzyme (ACE), takes part in the renin-angiotensin system. ACE2 counters the activity of ACE. The downstream effects of the two enzymes are opposite: ACE activity leads to vasoconstriction, oxidative stress, inflammation, and apoptosis, whereas ACE2 causes vasodilatation, angiogenesis and anti-inflammatory, anti-oxidative and anti-apoptotic effects. Reducing the oxidative stress secondary to the imbalance between ACE and ACE2 could be the best approach for the prevention and treatment of COVID-19.