Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits

Abstract

N-acetyl-l-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (l-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.

Keywords: AKI; Antioxidant; BAL; CF; CIN; COPD; GCL; GSH; GSH Px; GSSG; Glutathione; IPF; IV; N-acetyl-l-cysteine; N-acetylcysteine; N-aceytl-p-benzoquinonimine; NAC; NAPQI; ROS; acute kidney injury; bronchoalveolar lavage; chronic obstructive pulmonary disease; contrast-induced nephropathy; cystic fibrosis; glutamate cysteine ligase; glutathione; glutathione disulfide; glutathione peroxidises; idiopathic pulmonary fibrosis; intravenous; reactive oxygen species.