LAUSR

Objective To determine if orally dosed γ-glutamylcysteine (γ-GC) can increase cellular glutathione (GSH) levels above homeostasis. Many chronic and age-related disorders are associated with down-regulation, or impairment, of glutamate cysteine ligase (GCL). This suggests that γ-GC supply may become limiting for the maintenance of cellular GSH at the normal levels required to effectively protect against oxidative stress and any resulting physiological damage. Methods GSH levels were measured in lymphocytes of healthy, non-fasting participants before and after single oral doses (2 and 4 g) of γ-GC. Blood samples were immediately processed using high speed fluorescence-activated cell sorting to isolate 106 lymphocytes that were then assayed for GSH content. Results A single 2 g dose of γ-GC increased lymphocyte GSH content above basal levels (53±47%, p<0.01, n=14) within 90 min of administration. A randomized dosage (2 and 4 g γ-GC) crossover design was used to explore the pharmacokinetics of this GSH increase. In general, for both dose levels (n=9), GSH increased from initial basal levels over 3 h (tmax) before reaching maximum GSH concentrations (Cmax) that were near two (2 g γ-GC) to three (4 g γ-GC) fold basal levels (0.4 nmol/106 lymphocytes). Beyond tmax, GSH levels progressively declined reaching near basal levels by 5 h. The GSH half-life was between 2 and 3 h with exposure (AUC) to increased GSH levels of 0.7 (2 g γ-GC) and 1.8 (4 g γ-GC) nmol.h/106 lymphocytes. Conclusions Oral γ-GC is a non-toxic form of cysteine that can be directly taken up by cells and transiently increase lymphocyte GSH above homeostatic levels. Our findings that γ-GC can increase GSH levels in healthy subjects suggests that it may have potential as an adjunct for treating diseases associated with chronic GSH depletion. This trial was registered at anzctr.org.au as ACTRN12612000952842.