N-acetylcysteine Pharmacology and Applications in Rare Diseases—Repurposing an Old Antioxidant

Abstract

N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.

Chemical Composition, In Vitro Antitumor Effect, and Toxicity in Zebrafish of the Essential Oil from Conyza bonariensis (L.) Cronquist (Asteraceae)

“…In the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay, elevated levels of ROS were obtained after CBEO treatment. In addition, pretreatment with N-acetylcysteine (NAC), an antioxidant molecule [98], significantly reduced the CBEO cytotoxicity, corroborating the involvement of ROS in the antitumor effect induced by this EO. It has been reported that increased ROS production is a common event in EO-induced tumor cell death [99].…”

Alginate Oligosaccharides Protect Gastric Epithelial Cells against Oxidative Stress Damage through Induction of the Nrf2 Pathway

“…A similar significant effect (p < 0.0001-p < 0.05) was observed in GES-1 preincubated with 400 µg/mL AOS for 24 h, in which the intracellular ROS level of GES-1 decreased compared to that of the cells that were not treated with AOS (Figure 2B). As a positive control, we used N-acetylcysteine (NAc), which is a well-known pharmacological and antioxidant mechanism [40,41]. Five mM NAc was able to significatively recuperate (p < 0.0001) the normal intracellular ROS levels in cells exposed to 200 µM of peroxide.…”

In Vitro Investigation of the Effects of Various Reducing Agents on Dentin Treated with Hydrogen Peroxide

“…Non-protein thiols (NPSH) are potent antioxidants produced by the human body that help with a variety of biological processes [ 19 ]. Reduced glutathione (GSH), the active form of glutathione, is the most common NPSH, accounting for 90% of intracellular levels, whereas n -acetylcysteine (NAC) is one of the most bioavailable precursors of GSH [ 20 , 21 ]. The focus on NPSH in dentistry is not new; previous research found that particular NPSH, namely GSH and NAC, were efficient in mitigating the toxic effect of monomers on pulpal cells and inhibiting dentinal MMPs without affecting bonding to dentin [ 22 , 23 , 24 ].…”