N-Acetylcysteine (NAC)

N-Acetylcysteine (NAC) is a stable, acetylated derivative of the amino-acid L-cysteine. In the body, it serves primarily as a precursor for the antioxidant glutathione and as a mucolytic agent, making it widely used both clinically (e.g., acetaminophen toxicity, respiratory disorders) and as a dietary supplement for broader health support.

• Antioxidant support: NAC replenishes intracellular glutathione, reducing oxidative stress in conditions such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.
• Respiratory health: By breaking disulfide bonds in mucus, NAC improves airway clearance in COPD, bronchitis, and cystic fibrosis, with meta-analyses showing modest improvements in FEV₁ and symptom scores.
• Neuro-cognitive protection: Elevated brain glutathione levels after NAC supplementation have been linked to reduced depressive symptoms, attenuated neuro-inflammation, and modest cognitive improvements in schizophrenia and Alzheimer-type models.
• Metabolic regulation: NAC improves insulin sensitivity and attenuates hepatic steatosis in animal studies, and modest human trials show reductions in fasting glucose and markers of liver injury.
• Detoxification: NAC is the recommended antidote for acetaminophen overdose and supports detoxification pathways for heavy metals and environmental toxins.

• Process: NAC enters cells via the neutral amino-acid transport system (e.g., system L).
• Pathway: Once inside, the acetyl group is removed, yielding cysteine, which fuels the rate-limiting step of glutathione synthesis via γ-glutamylcysteine synthetase. Elevated glutathione (GSH) directly scavenges reactive oxygen species and serves as a co-factor for glutathione peroxidase, restoring redox balance. NAC also provides a sulfhydryl (-SH) group that directly reduces disulfide bonds in mucoproteins, thinning mucus. In the brain, NAC modulates the cystine-glutamate antiporter (system x_c⁻), increasing extracellular cystine and boosting glutamate uptake, which stabilizes neuronal excitability. Additionally, NAC influences the Nrf2/ARE pathway, up-regulating antioxidant enzymes, and may attenuate NF-κB–mediated inflammation.

• N-Acetylcysteine (IUPAC: (2-acetylamino)-3-mercaptopropanoic acid) has the molecular formula C₅H₉NO₃S and a molar mass of 163.19 g mol⁻¹.
• Molecular Structure: The molecule consists of a cysteine backbone with an acetyl group attached to the α-amino nitrogen, and a free thiol (-SH) on the β-carbon.
• Physical Properties: It is a water-soluble, white crystalline powder (pKa ≈ 9.5 for the thiol).
• Zwitterion: NAC is a zwitterion at physiological pH, enabling good oral absorption (≈ 70 % bioavailability).
• Reducing Properties: Its sulfhydryl group confers reducing properties, while the acetyl moiety protects the thiol from oxidation during storage.
• Stability: The molecule is stable under neutral pH but can oxidize to cystine if exposed to air, so antioxidants are often added to supplements.

• Commercial NAC is primarily produced by chemical synthesis from L-cysteine, which itself is derived from fermentation of glucose or other carbon sources using bacterial or fungal strains (e.g., E. coli).
• Acetylation: The acetylation step uses acetic anhydride or acetyl chloride under controlled conditions, yielding a highly pure (> 99 %) product.
• Natural Sources: Natural sources contain only trace amounts; dietary cysteine can be acetylated in vivo but dietary NAC is negligible.
• Supplement Manufacturing: For supplements, manufacturers must ensure Good Manufacturing Practice (GMP) compliance, verification of the absence of heavy metals, and a stable formulation (often as a sodium salt, NAC-Na) to enhance solubility.
• Third-Party Testing: Third-party testing (e.g., USP, NSF) is recommended to verify potency and purity, especially since the FDA has recently re-evaluated NAC’s status as a dietary ingredient.