Glutathione

Glutathione, abbreviated GSH, is built from glutamate, cysteine and glycine. No other small molecule carries as much of the antioxidant load in animal cells, and the scientific literature treats it as the master switch of the redox state inside the cell. One structural quirk explains its robustness: glutamate and cysteine are joined through a gamma bond that the usual peptide-cleaving enzymes slide off.

Its tasks interlock on several levels:

• As a direct reducing agent it mops up reactive oxygen species.
• For the glutathione peroxidases it serves as a cofactor.
• The glutathione S-transferases of phase II detoxification consume it as a substrate.

Preclinical work accordingly links GSH to oxidative stress, mitochondrial function, detoxification in the liver and signaling pathways of skin pigmentation. One review characterizes the mitochondrial pool as the first line of defense against oxygen radicals leaking from the respiratory chain.

A practical point dictates how it is studied: taken orally, the tripeptide is dismantled into its amino acids in the digestive tract. In a study with seven healthy volunteers, a single swallowed dose left the blood levels of the tripeptide and of its building blocks cysteine and glutamate essentially unchanged; since then the route through the stomach has been regarded as barely productive. Preclinical models therefore dose subcutaneously, intramuscularly or intravenously. Aging research discusses that cellular GSH levels fall with age, that this ties in with mitochondrial dysfunction, and that connections to sirtuins and NAD+ exist.

Since the body produces glutathione itself and relies on it as its main small antioxidant, studies rate tolerability as good. Even so:

• Large amounts per dose: At high doses, redness, pressure and a transient irritation at the injection site are among the most frequent observations.
• Shortly after dosing: Isolated reports describe a feeling of warmth or slight dizziness after parenteral administration.
• Skin tone: Through the documented effect on pigmentation pathways, repeated dosing can alter skin tone; the literature describes this as reversible.
• Missing long-term data: No robust human studies exist on prolonged, high-dose parenteral use. What is known derives from the molecule's physiological job, from animal work and from experience reports.

This summary is no substitute for medical advice.

• Glutathione: overview of its protective roles - review by Forman and colleagues on the protective mechanisms of the tripeptide.
• Glutathione metabolism and its implications in health - describes synthesis, breakdown and significance of glutathione metabolism.
• Mitochondrial glutathione, a key survival antioxidant - explains why the mitochondrial GSH pool is regarded as the main defense against radicals from the respiratory chain.
• The systemic availability of oral glutathione - study in seven volunteers showing that swallowed glutathione barely reaches the bloodstream.