by Jesse Davis, DC
Glutathione (GSH) is the most prominent endogenous antioxidant compound in the body. Due to the fact that it is created inside the body, it is not an essential nutrient. However, levels vary within tissues inside the body depending on the individual, and the various stresses and demands an individual is going through at a particular time. Because of glutathione’s key role, it exists in nearly every tissue in humans, as well as nearly all mammals.
Glutathione Structure and Function
The key role of glutathione in cells is primarily to act as a reducing agent to remove reactive oxygen species, such as those produced as a byproduct of cellular metabolism, as well as other free radicals. Glutathione also acts in the removal of toxins and drug compounds, which occurs primarily in the liver.
Glutathione acts namely through a mechanism that allows it to be recycled for future use. Its chemical makeup is as a sulfur containing tripeptide of glutamate, cysteine and glycine, with the sulfide group of cysteine being the primary-reactive portion. Upon accepting the negative charge from its target, glutathione binds (as glutathione disulfide, or GSSG) to another spent glutathione molecule, effectively dampening its charged impact. Glutathione reductase enzymes are primarily responsible for restoring it to its active state.
Since glutathione is a small peptide, it is readily broken down into its constituent amino acids through the digestive system when taken in orally. A large study found that ingestion of a considerable amount of oral glutathione for four weeks did not significantly change the oxidative stress levels (as measured by ratio of reduced to oxidized glutathione levels in erythrocytes) nor erythrocyte glutathione status.
Production of glutathione is thought to be largely regulated by the cysteine availability in the cells, as well as the enzymes involved in its assembly. N-acetylcysteine has been studied extensively in its role as a glutathione precursor. It’s ability to convert to measurable levels of increased glutathione has been found to correspond in large part to particular stressors, which are thought to increase need.
“The data show that NAC leads to a marked increase in circulating cysteine, in part by reacting with cystine and thereby forming mixed disulphides with cysteine and releasing free cysteine as shown in vitro. NAC had no effect on plasma glutathione in the absence of increased stress on the glutathione pools. However, NAC supports glutathione synthesis when the demand for glutathione is increased.”
Glutathione and Metabolic Toxins
A key role in metabolism for glutathione is to counter amounts of the metabolite methylglyoxal. Methylglyoxal is formed multiple ways in cells, but is primarily the result of normal glycolysis.
“Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal.”
The glyoxalase system, another system nearly ubiquitous to life forms, uses reduced glutathione as a cofactor in the processing of methylglyoxal, aiding in limiting amounts of this typically damaging substance.
Precursors and Acetaminophen Overdose
An example of the role glutathione plays intracellularly in detoxification is in pediatric acetaminophen overdose. Standard antidotes in the case of acetaminophen overdose in children is N-Acetylcysteine, a glutathione precursor. A WHO Review from 2008 stated the following on its use:
“Acetaminophen (paracetamol) toxicity is a common cause of drug-induced
hepatotoxicity in children and adults. N-acetylcysteine (NAC) has been used for several decades and has proven to be the antidote of choice in treating acetaminophen-induced hepatotoxicity”
Loss of Active Glutathione and Disease States
The Journal of Cellular Biochemistry in 2013 states “the loss of reduced glutathione and formation of glutathione disulfide is considered a classical parameter of oxidative stress that is increased in diseases.”  * There is widespread research findings that note how various disease states are associated with decreases in GSH. According to The Journal of Nutrition (Vol. 134, 3):*
“GSH displays remarkable metabolic and regulatory versatility. GSH/GSSG is the most important redox couple and plays crucial roles in antioxidant defense, nutrient metabolism, and the regulation of pathways essential for whole body homeostasis. Glutathione deficiency contributes to oxidative stress, and, therefore, may play a key role in aging and the pathogenesis of many diseases.”
A diet that is rich in vegetables in whole food form or powdered concentrates, especially garlic, onions and the cruciferous vegetables (broccoli, cauliflower, cabbage, collards, kale and watercress) is imperative in maintaining adequate antioxidant and folate levels that serve as precursors to glutathione.
As research draws more conclusions as to the role of glutathione and oxidative stress, practitioners are increasingly interested in how this powerful antioxidant may play a role in maintaining patient health and wellness.
-  Clinical Chemistry August 2001 vol. 47 no. 8 1467-1469
-  J Altern Complement Med. 2011 Sep; 17(9): 827–833.
-  Eur J Clin Pharmacol. 1989;36(2):127-31.
-  Front Neurosci. 2015 Feb 9;9:23.
-  Biochem. J.(1990)269,1-11
-  Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines Geneva, 29 September to 3 October 2008
REVIEW OF N-ACETYLCYSTEINE FOR THE TREATMENT OF ACETAMINOPHEN (PARACETAMOL) TOXICITY IN PEDIATRICS
-  J Cell Biochem. 2013 Sep;114(9):1962-8.
-  J. Nutr. March 1, 2004 vol. 134 no. 3 489-492
-  Nutrients. 2013 Dec 18;5(12):5218-32.
-  Nutr Cancer. 2011;63(3):367-75.
-  Nutrients. 2014, Sep 29;6(10):4002-31.