Evaluation of the Antioxidant Properties of N-acetylcysteine in Human Platelets: Prerequisite for Bioconversion to Glutathione for Antioxidant and Antiplatelet Activity

Abstract

N-Acetylcysteine (NAC) is a frequently used "antioxidant" in vitro, but the concentrations applied rarely correlate with those encountered with oral dosing in vivo. Here, we investigated the in vitro antioxidant and antiplatelet properties of NAC at concentrations (10-100 microM) that are achievable in plasma with tolerable oral dosing. The impact of NAC pretreatment (2 hours) on aggregation of platelets from healthy volunteers in response to thrombin and adenosine diphosphate and on platelet-derived nitric oxide (NO) was examined. NAC was found to be a weak reducing agent and a poor antioxidant compared with glutathione (reduced form) (GSH). However, platelets treated with NAC showed enhanced antioxidant activity and depression of reactive oxygen species generation associated with increases in intraplatelet GSH levels. An approximately 2-fold increase in NO synthase-derived nitrite was observed with 10 microM NAC treatment, but the effect was not concentration dependent. Finally, NAC significantly reduced both thrombin-induced and adenosine diphosphate-induced platelet aggregation. NAC should be considered a weak antioxidant that requires prior conversion to GSH to convey antioxidant and antithrombotic benefit at therapeutically relevant concentrations. Our results suggest that NAC might be an effective antiplatelet agent in conditions where increased oxidative stress contributes to heightened risk of thrombosis but only if the intraplatelet machinery to convert it to GSH is functional.

Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei

“…It is therefore surprising why NAC treatment at the current dosage did not sufficiently alter the oxidative load to register as an improvement in the GSH ratio. One explanation could be that NAC is a relatively weak antioxidant by itself, instead relying on conversion to the more potent antioxidant GSH to mediate its free radical scavenging effects [40]. Coupled with the low plasma concentrations achieved via oral supplementation, NAC may not contribute significantly to antioxidant defense in the diabetic patients [41].…”

Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway

“…Some studies show that NAC exhibits a concentration-dependent inhibition on ROS induction [30]. However, other studies demonstrate that NAC is a weak reducing agent and a poor antioxidant compared with glutathione (reduced form) (GSH) [31,32]. …”

Ru(III)-catalyzed oxidation of N-acetyl-L-cysteine by methylene blue in absence and in presence of Cu(II) in acidic medium: influence of solvent and morphology

“…[1,2] NAC, reported to be a precursor of glutathione biosynthesis, [3] is a drug which has potential for treating cancer, Alzheimer's disease, metal toxicity and cardiovascular diseases. [4][5][6] The mode of action of this drug is by and large shown to be related to the thiol or thiolate moiety of the molecule and one of the regulatory features of this moiety is metal complex formation. [3] Biomolecules such as cysteine and glutathione bind to Ru(II) and Ru(III) centers through the sulfhydryl group.…”