N-acetylcysteine Amide (NACA), a Novel GSH Prodrug: Its Metabolism and Implications in Health

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH), the most abundant non-protein thiol, plays a pivotal role in various cellular functions. Glutathione deficiency leads to oxidative stress which is implicated in aging and in a number of pathologies, including Alzheimer\u27s disease, Parkinson\u27s disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes. Since GSH cannot be replenished directly due to its unfavorable biochemical and pharmacokinetic properties, a logical approach to enhancing antioxidant protection would be the use of GSH prodrugs. GSH may be increased by supplying GSH prodrugs like esters of GSH, γ-glutamyl cysteine, cysteine, cysteine esters, and N-acetylcysteine (NAC). However, large doses of these prodrugs are required due to their poor bioavailability and toxicity which limit their use as a therapeutic agent. A potential candidate that possesses far better characteristics for development as a GSH prodrug to address oxidative damage is the low molecular weight thiol antioxidant, N-acetylcysteine amide (NACA). NACA\u27s characteristics as a drug were improved over NAC by neutralizing the carboxylic group of NAC, which makes the NACA molecule more lipophilic and, therefore, enhances its ability to penetrate cellular membranes. The enhanced ability to penetrate cells allows NACA to be administered at a lower dose than NAC, giving the drug a greater therapeutic index and lowering the risk of side effects that traditionally have been associated with higher doses of NAC. NACA is an excellent source of sulfhydryl (SH) groups that can be converted by the cells into metabolites capable of stimulating glutathione synthesis. The molecule can also promote intracellular detoxification and act directly as a free radical scavenger. NACA functions as a carrier of NAC and its antioxidant and free radical scavenging abilities are equal to or better than those of NAC. Promising results with NACA have provided additional momentum for research on GSH prodrug-based approaches to treat oxidative stress-related disorders. This chapter will focus on the role of NACA in protection against oxidative damage by increasing GSH levels in numerous Oxidative Stress -related diseases