title: Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study.
abstract: 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.
  
  
  
  GSH levels were measured in lymphocytes of healthy, non-fasting participants before and after single oral doses (2 and 4g) of γ-GC. Blood samples were immediately processed using high speed fluorescence-activated cell sorting to isolate 106lymphocytes that were then assayed for GSH content.
  
  
  
  A single 2g dose of γ-GC increased lymphocyte GSH content above basal levels (53±47%, p<0.01, n=14) within 90min of administration. A randomized dosage (2 and 4g 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 3h (tmax) before reaching maximum GSH concentrations (Cmax) that were near two (2g γ-GC) to three (4g γ-GC) fold basal levels (0.4 nmol/106lymphocytes). Beyond tmax, GSH levels progressively declined reaching near basal levels by 5h. The GSH half-life was between 2 and 3h with exposure (AUC) to increased GSH levels of 0.7 (2g γ-GC) and 1.8 (4g γ-GC) nmol.h/106lymphocytes.
  
  
  
  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.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Martin Hani
authors.initials: MH
authors.lastname: Zarka
authors.affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia. Electronic address: wj.bridge@unsw.edu.au.
authors.forename: Wallace John
authors.initials: WJ
authors.lastname: Bridge
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004151:Dipeptides / Q000008:administration & dosage*; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000097:blood*; D005978:Glutathione / Q000097:blood*; D064368:Healthy Volunteers; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
chemical_list: D004151:Dipeptides; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C017341:gamma-glutamylcysteine
keywords: Clinical trial; Glutamylcysteine; Glutathione; Homeostasis