Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study

Abstract

ObjectiveTo 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.MethodsGSH 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.ResultsA 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.ConclusionsOral 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.

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“…Besides NAC, γ‐glutamylcysteine, another GSH precursor, and 2‐oxothiazolidine‐4‐carboxylate (OTC), an analogue of 5‐oxproline, also seem to have the potential to increase endogenous GSH levels. Both γ‐glutamylcysteine and OTC increased GSH and reduced oxidative stress in experimental and clinical studies . Similar to NAC, supplementation of γ‐glutamylcysteine increased the levels of GSH in patients with cancer, with no adverse effects .…”

“…Both γ‐glutamylcysteine and OTC increased GSH and reduced oxidative stress in experimental and clinical studies . Similar to NAC, supplementation of γ‐glutamylcysteine increased the levels of GSH in patients with cancer, with no adverse effects . OTC, which is converted to cysteine by 5‐oxoprolinase (OPLAH), increased GSH levels in the experimental setting .…”

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“…Animal safety trials have demonstrated that GGC is safe at repeated doses at a limit dosage of 1000 mg/kg over a 90-day period [12]. No adverse effect was observed in a human clinical trial of healthy, non-fasting subjects [13]. Single dose of oral administered GGC at 2 g and 4 g is bioavailable and can increase intracellular GSH levels above homeostasis in lymphocytes.…”

“…Products containing GGC for oral consumption are now on sale to the general public in the USA. An oral route of delivery allows for rapid first pass metabolism of GGC via the gut and liver and a subsequent increase in circulating GGC [13]. Defects in gut and liver function in CF patients, however, could hamper oral GGC efficacy.…”

“…Animal safety trials have demonstrated that GGC is safe at repeated doses at a limit dosage of 1000 mg/kg over a 90-day period [12]. A randomised human pilot study found that single doses of oral administered GGC at 2 g and 4 g significantly increased GSH levels in lymphocytes within 3h, with a return to normal homeostatic levels by 5h [13]. Recently, anti-oxidative and anti-inflammatory properties have been demonstrated for GGC in astrocytes (7,21) and in vivo in a mouse sepsis model (19).…”