N-Acetylcysteine (NAC) is the amino acid derivative that is the most effective oral booster of the cellular glutathione levels — it is a precursor of the cysteine, which is the rate-limiting amino acid for the synthesis of the glutathione (the most important intracellular antioxidant in the human body). The glutathione (GSH) is the tripeptide (gamma-glutamyl-cysteinyl-glycine) that is present in all cells at millimolar concentrations (1-10mM), and it is the primary defence against the oxidative stress, the electrophilic toxins, and the reactive nitrogen species. The glutathione is the substrate for the glutathione peroxidase (which reduces the hydrogen peroxide and the lipid peroxides to water and to the corresponding alcohols, thereby preventing the oxidative damage to the cell membranes and to the DNA), for the glutathione S-transferases (which conjugate the electrophilic toxins and facilitate their excretion), and for the gamma-glutamyl transpeptidase (which is involved in the maintenance of the intracellular cysteine levels and in the immune function). The glutathione levels decline with age (by 30-40% between the ages of 30 and 70), and this decline is one of the primary drivers of the age-related increase in the oxidative stress and in the susceptibility to the toxins and the infections. The NAC is the most effective oral precursor of the glutathione because it is rapidly absorbed from the intestine, it is deacetylated to the cysteine in the liver, and it is available for the glutathione synthesis in all tissues. Without adequate NAC and glutathione, the antioxidant defence is impaired, the oxidative stress increases, and the liver and other tissues are vulnerable to the toxic damage — the hallmark of the NAC deficiency and of the low glutathione states (which are associated with the ageing, the chronic diseases, and the exposure to the environmental toxins).
NAC and the Liver Protection
NAC is best known for its role in the protection of the liver from the toxic damage — it is the standard of care for the acetaminophen (paracetamol) overdose, and it is used in the hospital setting to prevent the liver failure in people who have ingested potentially hepatotoxic doses of the acetaminophen. The mechanism of the NAC’s hepatoprotective effect involves the restoration of the glutathione levels in the liver (which are depleted by the acetaminophen metabolites, particularly the N-acetyl-p-benzoquinone imine, NAPQI, which is the toxic metabolite that is formed by the CYP2E1-mediated oxidation of the acetaminophen). By restoring the glutathione levels, the NAC enables the liver to conjugate the NAPQI and to excrete it as the non-toxic mercapturic acid conjugate, thereby preventing the covalent binding of the NAPQI to the hepatic proteins and the subsequent hepatocyte death and liver failure. The NAC also protects the liver through its antioxidant effects (scavenging the reactive oxygen species that are generated by the drug metabolism and by the inflammatory response), through its anti-inflammatory effects (inhibiting the NF-kappaB and the pro-inflammatory cytokines), and through its vasodilatory effects (increasing the blood flow to the liver and to the kidneys and facilitating the excretion of the toxins).
The clinical importance of the NAC for the liver protection is underscored by the observation that the NAC supplementation improves the liver function and reduces the oxidative stress in people with the non-alcoholic fatty liver disease (NAFLD) and in people with the chronic hepatitis C. A meta-analysis of 5 RCTs in 300 participants found that the NAC supplementation at 600-1800mg daily for 3-6 months significantly reduced the ALT levels (by 15-20%), reduced the AST levels (by 10-15%), and reduced the oxidative stress markers (by 20-30%, as measured by the malondialdehyde and the 8-hydroxy-2-deoxyguanosine) — making the NAC one of the most effective interventions for the NAFLD and for the general liver support.
Practical Application
For general NAC supplementation for the glutathione support and for the liver protection, the evidence-based approach is to supplement with 600-1800mg of NAC daily (in divided doses of 600mg, taken 2-3 times per day). The NAC should be taken on the empty stomach (30-60 minutes before the meals or 2 hours after the meals) for the optimal absorption. The NAC is generally well-tolerated with no significant adverse effects at doses up to 3000mg daily, though it may cause the gastrointestinal symptoms (nausea, diarrhoea) at the high doses, and it has a strong sulfur smell that some people find unpleasant. For comprehensive glutathione and liver support, NAC pairs well with the selenium (which is a cofactor for the glutathione peroxidase and which works synergistically with the NAC for the antioxidant defence), with the vitamin E (which works in concert with the glutathione for the lipid antioxidant defence), with the alpha-lipoic acid (which is another antioxidant that works through a complementary mechanism and which helps to regenerate the glutathione), and with the milk thistle/silymarin (which is a potent hepatoprotective compound that works synergistically with the NAC for the liver protection).
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