What is glutathione?

Glutathione: A Critical Antioxidant Tripeptide

Glutathione (GSH) is a tripeptide composed of three amino acids—glutamic acid, cysteine, and glycine—that functions as the predominant intracellular antioxidant in humans, protecting cells against oxidative damage, toxicity from xenobiotics, and maintaining redox homeostasis. 1

Chemical Structure and Forms

• Glutathione exists in two main forms: reduced glutathione (GSH) and oxidized glutathione (GSSG), where two GSH molecules combine via sulfhydryl bonds 1
• The chemical structure consists of gamma-glutamyl-cysteinyl-glycine, with the unusual gamma peptide linkage between glutamate and cysteine contributing to its stability against enzymatic degradation 2

Biological Functions

Primary Antioxidant Role

• GSH serves as a major cellular defense against reactive oxygen species (ROS), lipid hydroperoxides, and free radicals 1
• It functions as an electron donor to reduce oxidative compounds, converting to its oxidized form (GSSG) in the process 2
• The GSH/GSSG ratio is a critical indicator of cellular redox status and oxidative stress 3

Detoxification Mechanisms

• GSH participates in detoxification reactions through glutathione peroxidase (GPX), which reduces hydrogen peroxide and lipid peroxides 1
• Glutathione-S-transferase (GST) catalyzes the conjugation of GSH with xenobiotics and electrophilic compounds, facilitating their elimination 2
• The glutathione reductase (GR) enzyme maintains cellular GSH levels by converting GSSG back to GSH using NADPH as a cofactor 1

Biosynthesis and Regulation

• GSH is synthesized intracellularly through a two-step ATP-dependent process 3
• The first and rate-limiting step is catalyzed by gamma-glutamylcysteine synthetase, followed by the addition of glycine by glutathione synthetase 3
• Cysteine availability is typically the limiting factor in GSH synthesis 4
• Synthesis is regulated through feedback inhibition, with high GSH levels inhibiting gamma-glutamylcysteine synthetase 3

Clinical Significance

Role in Disease States

• Altered glutathione homeostasis serves as a potential marker for various human diseases 5
• GSH depletion is associated with increased oxidative stress and cellular damage in conditions such as cancer, neurodegenerative diseases, and aging 2
• In ferroptosis (a form of regulated cell death), glutathione peroxidase 4 (GPX4) plays a major role in inhibiting lipid peroxidation 6

Dual Role in Cancer

• GSH exhibits a dual role in cancer: it can protect against carcinogenesis by removing carcinogenic compounds through GST activity 1
• However, elevated GSH levels in cancer cells can confer resistance to chemotherapy and radiotherapy by neutralizing oxidative stress induced by these treatments 1
• GSH inhibitors like buthionine sulfoximine have been studied to improve chemosensitivity in cancer cells 1

Therapeutic Applications

• Supplementation with GSH precursors (cysteine, glycine, and glutamate) can enhance tissue GSH synthesis when endogenous production is insufficient 4
• N-acetylcysteine (NAC) serves as a cysteine donor and has been shown to inhibit eryptosis (programmed death of red blood cells) in vitro and prolong erythrocyte half-life in vivo 6
• In clinical settings, glutamine supplementation (0.3-0.5 g/kg/day) is recommended for patients with burns >20% body surface area, as it serves as a precursor for glutathione synthesis 6

Measurement and Assessment

• Assessment of glutathione status can be performed through measurement of GSH/GSSG ratios in blood or tissues 2
• Whole blood selenium measurement provides insight into glutathione peroxidase activity, as selenium is an essential component of these enzymes 6
• Challenges remain in the in situ quantification of endogenously produced glutathione, limiting understanding of exogenous glutathione bioprocessing 5

Dietary Sources and Supplementation

• Glutathione is present in various plant and animal cells, though concentrations vary considerably 5
• Direct oral GSH supplementation has limited efficacy due to enzymatic degradation by γ-glutamyltransferase in the intestine 4
• Supplementation with precursor amino acids (particularly cysteine) is more effective for enhancing tissue GSH synthesis 4
• Certain dietary patterns and micronutrient intake can influence GSH homeostasis and redox status 4

Clinical Applications in Critical Care

• In critically ill patients, glutamine serves as an important precursor for glutathione synthesis 6
• Glutamine supplementation (0.2-0.3 g/kg/day) is recommended for critically ill trauma patients with complicated wound healing 6
• However, glutamine supplementation is not recommended for general ICU patients except those with burns or trauma 6
• Parenteral glutamine should not be administered in unstable ICU patients with liver and renal failure 6