How does injectable glutathione (GSH) work?

How Injectable Glutathione Works

Injectable glutathione (GSH) functions primarily as a direct antioxidant by serving as a cofactor for glutathione peroxidase, which reduces lipid peroxides and hydrogen peroxide to prevent oxidative cellular damage, though no medical guidelines or high-quality research support subcutaneous administration—only intravenous routes have established evidence. 1

Fundamental Biochemical Mechanisms

Primary Antioxidant Function

• GSH acts as the most abundant endogenous antioxidant in cells (1-10 mM concentration), maintaining cellular redox balance by existing primarily in its reduced thiol form (>98% of total GSH). 2
• The tripeptide structure (γ-L-glutamyl-L-cysteinyl-glycine) enables GSH to directly neutralize reactive oxygen species (ROS), reactive nitrogen species, and reactive sulfur species through electron donation. 3, 2
• GSH serves as an essential cofactor for glutathione peroxidase (GPX4), which catalyzes the reduction of hydrogen peroxide (H₂O₂) to water and lipid peroxides (PLOOH) to lipid alcohols, preventing membrane damage and ferroptosis. 4

Cellular Protection Pathways

• Glutathione peroxidase requires selenium for optimal enzymatic activity, making adequate selenium status crucial for GSH function. 5
• GSH protects against lipid peroxidation by converting oxidized glutathione disulfide (GSSG) back to its reduced form through glutathione reductase, which requires NADPH as a cofactor. 4
• The GSH/GSSG ratio serves as a critical indicator of cellular redox status and oxidative stress levels, with decreased ratios indicating oxidative damage. 6, 2

Systemic Effects After Injectable Administration

Bioavailability and Distribution

• Intravenous liposomal GSH administration (500-1000 mg/day) elevates GSH levels by 40% in whole blood, 25% in erythrocytes, 28% in plasma, and 100% in peripheral blood mononuclear cells within 1-2 weeks. 6
• Injectable GSH bypasses the gastrointestinal degradation that limits oral bioavailability, allowing direct systemic distribution. 6
• GSH distributes to tissues where it participates in detoxification reactions through glutathione S-transferase (GST)-catalyzed conjugation of electrophilic compounds. 4

Oxidative Stress Reduction

• Injectable GSH reduces plasma 8-isoprostane (a lipid peroxidation marker) by 35% and decreases oxidized:reduced GSH ratios by 20% within 2 weeks. 6
• GSH activates the Keap1-Nrf2-ARE pathway by releasing Nrf2 transcription factor, which upregulates genes controlling antioxidant enzyme expression, inflammatory responses, and immune function. 2
• Erythrocytes rely heavily on GSH for survival since they lack mitochondria and peroxisomes but contain high iron levels from hemoglobin, making them vulnerable to oxidative stress. 4

Immune System Modulation

• Injectable liposomal GSH enhances natural killer (NK) cell cytotoxicity by up to 400% and increases lymphocyte proliferation by 60% after 2 weeks of administration. 6
• GSH depletion impairs immune system function and is implicated in disease severity for conditions like HIV, tuberculosis, and COVID-19. 7, 2

Clinical Context-Specific Mechanisms

Chemotherapy Neuroprotection (Mixed Evidence)

• For platinum-based chemotherapy (cisplatin/oxaliplatin), injectable GSH (1.5-2.5g IV before chemotherapy) may reduce peripheral neuropathy through detoxification of platinum-induced reactive intermediates, though five small trials showed benefit while one larger trial with paclitaxel/carboplatin showed no benefit. 4, 1
• The American Society of Clinical Oncology states GSH is ineffective for taxane-induced neuropathy prevention, suggesting the mechanism differs between platinum and taxane neurotoxicity. 4, 1

Cellular Detoxification

• GSH conjugates with toxic metabolites and xenobiotics through GST enzymes, creating water-soluble compounds that are transported out of cells, protecting against chemical-induced cellular damage. 4, 3
• Different GST isoenzymes (Alpha, Mu, Pi, Theta, Zeta) exhibit varying catalytic efficiency for different substrates, with some showing preference for specific carcinogenic metabolites. 4

Critical Safety Limitations

Route-Specific Concerns

• No pharmacokinetic data exists for subcutaneous bioavailability of glutathione, and no sterile pharmaceutical-grade formulations are designed for subcutaneous use. 1
• Subcutaneous administration carries risks of injection site reactions, tissue irritation, abscess formation, and unknown systemic absorption rates. 1
• Only intravenous administration has established evidence in medical literature—subcutaneous injection is not discussed in any guideline or high-quality research. 1

Clinical Pitfalls

• During active cancer treatment, most oncologists advise against high-dose antioxidant supplementation (including GSH) during chemotherapy or radiotherapy, as antioxidants may protect cancer cells from oxidative damage that contributes to treatment effectiveness. 8
• GSH should not be confused with glutamine—they are different compounds with distinct indications and dosing regimens. 1
• For cystic fibrosis patients, no data supports glutathione therapy and supplementation is not recommended. 1