Dietary γ-Glutamylcysteine: Its Impact on Glutathione Status and Potential Health Outcomes

Abstract

Glutathione (GSH) is a tripeptide that is readily synthesized intracellularly in humans and other mammals. More than a century of research suggests that GSH has numerous biological functions, including protection from the potential adverse events associated with reactive oxygen species (ROS) and related redox reactions that may induce oxidative stress, and that may be linked to innate detoxification processes. Normal tissue and plasma levels of GSH decline through the aging process and decrease during various disease states. While the health value of dietary GSH remains controversial, there is evidence that some metabolic intermediates, such as γ-glutamylcysteine (GGC) may function to preserve adequate GSH levels when the synthetic pathways decline in activity, and the innate antioxidant system is challenged. It is also important to recognize that among the thousands of protein-coding human genes and their respective polymorphisms, at least two genes (Gclc and Gclm) are directly involved with GSH synthesis via glutamate-cysteine ligase. This commentary examines the classic biochemistry, toxicology, safety, and clinical value of GSH and its intermediates that may be modulated by dietary supplementation.

Keywords:

• Glutathione
• γ-glutamylcysteine
• N-acetylcysteine

Declaration of interest

Drs Pressman, Hayes and Clemens declare no conflicts of interest. Drs Bridge and Zarka are co-inventors on granted patents describing the manufacture of gamma glutamylcysteine.

Additional information

Funding

None.

Notes on contributors

Peter Pressman, MD

Dr. Peter Pressman, MD, MS, FACN was trained at Northwestern University, the University of Chicago, and Rush-Presbyterian St. Lukes Medical Center in Chicago. He served as a Naval Medical Officer and has extensive experience addressing malnutrition in conflict zones in the Middle East, Central Asia, and in the developing world in sub-Saharan Africa. Pressman pursued his interests in medical nutrition at the University of Southern California, as Associate Director of the Internal Medicine Residency Program and Director of Educational Programs of the Pacific Center for Health Policy & Ethics. Subsequently, in collaboration with Dr. Roger Clemens, he has published papers and book chapters in the realm of medical nutrition and public health, and co-taught the nutrition course in the Global Medicine Program at USC's Keck School of Medicine. He currently holds positions with The Daedalus Foundation and Polyscience Consulting.

Wallace John Bridge

Wallace Bridge, PhD, has 36 years R&D biotechnology experience in industry and academia. Since 1997, one of his major research focuses has involved glutathione. Initially, this involved the development of manufacturing processes for both glutathione whilst he was in industry and its immediate precursor, gamma glutamylcysteine (GGC) after he joined the University of New South Wales (UNSW). Following the establishment of a GGC manufacturing process, his work has progressed to investigating the unique potential of GGC to increase cellular glutathione levels and treat oxidative stress related disorders. His peer review publications discuss how dysfunctions in the enzyme glutamate cysteine ligase (GCL) lead to declines in cellular glutathione levels and introduce GGC's therapeutic potential. The oral administration bioavailability of GGC to systemically increase cellular glutathione levels was demonstrated in a UNSW sponsored human study. UNSW in vitro studies have demonstrated that GGC can increase cellular glutathione levels and improve markers of oxidative stress in human astrocytes and cystic fibrosis. The therapeutics potential of GGC was recently demonstrated in a mouse model for Alzheimer's disease. Ongoing GGC investigations at UNSW include mechanistic invitro cystic fibrosis studies, therapeutic animal models for a range of neurodegenerative disorders and autism, and in vitro studies exploring GGC's therapeutic potential against human respiratory RNA viruses.

Martin Hani Zarka

Dr. Martin Zarka earned his PhD at the University of New South Wales, School of Biotechnology and Biomolecular Sciences. He has collaborated closely with Dr. Bridge and currently is the Director of Research and Development at Biospecialties International, Australia Pty Ltd.

A. Wallace Hayes

Dr. Hayes holds degrees from Auburn University (Ph.D. and MS) and Emory University (AB). He was an NSF predoctoral fellow at Auburn University, an NIH individual postdoctoral fellow at the Vanderbilt University School of Medicine, a NATO Senior Scientist at the Central Veterinary Laboratory in Weybridge, England, and held an NIH Research Career Development Award. Dr. Hayes has held Professorships at the University of Alabama, the University of Mississippi Medical Center, Wake Forest University School of Medicine, Harvard School of Public Health, Michigan State University, and currently is Adjunct Professor, College of Public Health, University of South Florida. Dr. Hayes has authored more than 320 peer-reviewed publications, is the editor of Hayes' Principles and Methods of Toxicology, 6th edition, Human and Experimental Toxicology, Cutaneous and Ocular Toxicology, Toxicology Research and Application and the co-editor of the Target Organ Toxicity Series of books. Dr. Hayes is the Editor-in-Chief emeritus, Food and Chemical Toxicology and the co-author of Loomis' Essential of Toxicology, 5th Edition. Dr. Hayes is a past Secretary-General of IUTOX (two terms), past board member of the American Board of Toxicology, a past president of the American College of Toxicology, the Toxicology Education Foundation, and the Academy of Toxicological Sciences and a past member of the council of the Society of Toxicology. He is currently the President of the Toxicology Forum. Dr. Hayes is a diplomate of the American Board of Toxicology, the Academy of Toxicological Sciences, the American Board of Forensic Medicine, and the American Board of Forensic Examiners. He is a Fellow of the Academy of Toxicological Sciences, the Royal Society of Biology (UK), the American College of Forensic Examiners, and the American College of Nutrition. Dr. Hayes is a registered toxicologist in the European Union (ERT) and a certified nutrition specialist (food safety).

Roger Clemens

Professor Roger A. Clemens, DrPH, FIFT, CFS, FASN, FACN, CNS, FIAFST is Associate Director of the Regulatory Science program and Adjunct Professor of Pharmacology and Pharmaceutical Sciences within the USC School of Pharmacy. Dr. Clemens was the Director of Analytical Research at USC for 5 years, and the Scientific Advisor for Nestle USA for more than 21 years. He has published more than 50 original manuscripts in nutrition and food science, participated in more than 200 invited domestic and international lectures, and served as an expert panel member for the food industry, scientific organizations, trade associations and regulatory agencies in the United States and Canada.