Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.
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.
Highland Clinical Research Facility, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK.
Gordon F
GF
Rushworth
Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, UK. Electronic address: ian.megson@uhi.ac.uk.
Ian L
IL
Megson
D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use
D000975:Antioxidants; D011355:Prodrugs; D005978:Glutathione; D000111:Acetylcysteine
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