Glutathione

Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine, linked by an unusual gamma peptide bond between the gamma-carboxyl group of glutamate and the amino group of cysteine. It is the most abundant non-protein thiol in mammalian cells, with intracellular concentrations ranging from 1-10 mM. Present in virtually every cell in the body, it functions as the principal intracellular antioxidant and plays critical roles in detoxification, immune function, and cellular homeostasis.

Unlike most peptides discussed in research databases, glutathione is an endogenous compound with well-established biochemistry. Its clinical relevance stems from the observation that glutathione levels decline with age and are depleted in numerous disease states including HIV/AIDS, liver disease, neurodegenerative disorders, and pulmonary conditions. Exogenous supplementation strategies — including direct administration, precursor supplementation (NAC), and liposomal delivery — are areas of active clinical investigation.

Glutathione functions through its free sulfhydryl group on the cysteine residue, which serves as an electron donor for reduction reactions. In its primary antioxidant role, glutathione peroxidase uses GSH to reduce hydrogen peroxide and lipid hydroperoxides, generating oxidized glutathione (GSSG) in the process. GSSG is recycled back to GSH by glutathione reductase using NADPH, maintaining the cellular GSH:GSSG ratio above 100:1 under normal conditions. A declining ratio is a reliable marker of oxidative stress.

Beyond direct antioxidant activity, glutathione is essential for Phase II detoxification. Glutathione S-transferases conjugate GSH to electrophilic xenobiotics and endogenous toxins, rendering them water-soluble for excretion. The peptide also serves as a cysteine reservoir, participates in leukotriene and prostaglandin synthesis, and is required for proper T-cell proliferation and NK cell cytotoxicity. Immune cells are particularly sensitive to glutathione depletion — even modest reductions impair lymphocyte function and shift cytokine balance from Th1 (cell-mediated) toward Th2 (humoral) immunity.