Glutathione (GSH; γ-glutamyl-cysteinyl-glycine) is the major intracellular antioxidant + xenobiotic conjugator. Synthesis: glutamate + cysteine → γ-glutamylcysteine via γ-glutamylcysteine synthetase (γ-GCS) — RATE-LIMITING, inhibited by GSH (negative feedback). γ-GC + glycine → GSH (GSS). Redox cycle: GSH + ROS → GSSG (oxidized) via glutathione peroxidase (selenium cofactor); GSSG → GSH via glutathione reductase (NADPH from PPP). Acetaminophen toxicity: NAPQI (CYP2E1 metabolite of APAP, normally <5% of dose) depletes hepatic GSH; once GSH falls below ~30% of baseline, NAPQI covalently binds liver proteins → centrilobular necrosis. N-ACETYLCYSTEINE rescues by replenishing cysteine for GSH synthesis (most effective <8h post-ingestion).
Organ Systems
immune-hematologic
digestive
integumentary
Pathway Steps
glutamate → gamma-glutamylcysteine — via γ-glutamylcysteine synthetase (γ-GCS) — RATE-LIMITING; GSH feedback inhibition. γ-glutamylcysteine ligase (GCL) is the rate-limiting step, feedback-inhibited by glutathione; cysteine is usually the limiting substrate — the rationale for N-acetylcysteine (NAC) to replenish GSH, e.g. in acetaminophen overdose.
gamma-glutamylcysteine → glutathione — via glutathione synthetase (GSS). Glutathione synthetase adds glycine to complete the tripeptide. GSH’s unusual γ-glutamyl bond resists ordinary peptidases, so it is broken down only by γ-glutamyl transferase (GGT) — itself a clinical marker of hepatobiliary and oxidative stress.
glutathione → glutathione-disulfide — via glutathione peroxidase (GPx) — selenium cofactor; ROS detox. Glutathione peroxidase uses two GSH to reduce peroxides (H₂O₂, lipid peroxides) to water, forming oxidized GSSG — the cell’s principal aqueous antioxidant defense. GPx is a selenoenzyme, tying selenium status to antioxidant capacity.
glutathione-disulfide → glutathione — via glutathione reductase (GR) — NADPH consumer (PPP-fed). Glutathione reductase regenerates reduced GSH from GSSG using NADPH — supplied largely by the pentose-phosphate pathway, which is why G6PD deficiency impairs GSH recycling and causes oxidant-induced hemolysis. The GSH:GSSG ratio is a core redox readout.
Known Modulators
acetaminophen (inhibitor) — GSH depletion via NAPQI (toxic dose only)
nac (substrate) — intracellular cysteine pool — rate-limiting for GSH synthesis. N-acetylcysteine deacetylates to cysteine, the rate-limiting precursor for γ-glutamylcysteine + GSH (γ-glutamylcysteine synthetase reaction).