Which is more effective, oral, intramuscular or intravenous glutathione?

What is glutathione?

Glutathione (GSH) is the most abundant endogenous antioxidant in the human body. It can be synthesized by the human body itself and is a small molecule protein (tripeptide) composed of three amino acids (glutamic acid, cysteine, and glycine).

Glutathione is present in almost every cell, with the highest concentrations in the liver, immune cells and mitochondria.

Among them, mitochondrial GSH accounts for 10-15% of the total, but it is particularly crucial for energy metabolism.

Glutathione circulates dynamically in two forms: reduced (GSH) and oxidized (GSSG).

• Reduced Glutathione: An active "antioxidant form".

• Oxidized Glutathione: The "waste form" after use, which requires recycling with enzymes, vitamin C/ lipoic acid, etc.

five core functions of glutathione

1. Direct antioxidation

The antioxidant effect of glutathione (GSH) can be understood through a "three-step cycle" :

(1)captures free radicals

The thiol group (-SH) of GSH acts like a "magnet", directly reacting with free radicals (ROS/RNS), converting them into stable molecules, and itself being oxidized into oxidized glutathione (GSSG).

(2)recycling

Glutathione reductase (GR) uses NADPH (a coenzyme from vitamin B3) to re-reduce GSSG to GSH, forming an "antioxidant cycle" to ensure the continuous availability of GSH.

(3)synergy

• In collaboration with vitamin C: GSH helps reduce oxidized vitamin C, enabling it to continue scavenging free radicals.

• In collaboration with glutathione peroxidase (GPx) : GPx utilizes GSH to reduce lipid peroxides (such as MDA and F2-IsoPs) into harmless alcohols.

In a nutshell:

Glutathione acts like a "mobile fire extinguisher", first putting out the fire source (free radicals), then recharging itself (regenerating), and teaming up with other antioxidants to form an efficient "fire-fighting network".

Detoxification and metabolism

The "detoxification and metabolism" function of glutathione (GSH) can be broken down into four consecutive steps, simply referred to as the "grasping - binding - transporting - excreting" four-step process, all of which are completed in the liver (with a small amount in the kidneys and intestines).

1. Grab

Identify electrophilic poisons

By-products of alcohol metabolism (acetaldehyde, formaldehyde), heavy metals, drugs (acetaminophen), mycotoxins (aflatoxin B1), etc. all have "electron-deficient" centers.

These poisons are highly prone to bind to proteins /DNA → cell necrosis or mutation.

2. Binding

Covalent binding

Glutathione S-transferase (GST) catalyzes the formation of sulfide bonds between the sulfhydryl group (-SH) of GSH and the electrophilic center of the poison → generating the "GSH-poison complex".

The poison is "labeled", and its water solubility instantly increases by 5 to 50 times.

3. Transportation

Step-by-step cutting

The complex was hydrolyzed successively by Y-glutamyl transpeptidase (GGT) and dipeptidase to remove Glu and Gly, leaving cysteinyl-toxin.

The product is called mercapturic acid, which has smaller molecules and is easier to penetrate membranes.

4. Row

Bile or urine is excreted

The MRP2 transporter on the liver cell membrane pumps the final product into bile. If the molecular weight is less than 400 Da, it is excreted into urine through the renal tubules.

The poison was completely expelled from the body.

One-sentence memory

Glutathione is like a "garbage baler in cells" : first, it labels the toxins (grab - bind), then compresses and packs them (transport), and finally puts them on the garbage truck (dump) - the entire process cannot do without the three-piece set of GSH, GST enzyme system and NADPH energy.

Immune regulation

The immunomodulatory effect of glutathione (GSH) can be summarized as "two protections and three balances" - it not only protects immune cells from oxidation themselves but also balances the "intensity, direction and duration" of the immune response.

The latest review and clinical research evidence are as follows:

1. Protect the "hardware" of immune cells

Immune cells (T cells, B cells, macrophages) will explosively produce ROS when activated.

Glutathione, as the endogenous antioxidant with the highest intracellular concentration, can neutralize these ROS, prevent mitochondrial damage, DNA breakage and apoptosis.

The blood GSH level of HIV patients decreases, accompanied by a reduction in CD4⁺ T cell count.

After supplementing NAC or liposome GSH, the GSH content in CD4⁺ T cells increased, and the oxidative stress indicators decreased.

2. Balancing cytokine "software"

• Inhibiting excessive inflammation: GSH depletion activates NF-κB, leading to a sharp increase in TNF-α, IL-6, and IL-1β. After the restoration of GSH, the above pro-inflammatory factors decreased significantly, while the anti-inflammatory factor IL-10 increased.

• Correct Th drift: GSH deficiency leads to excessive polarization of Th1/Th17, which is prone to induce autoimmunity; Supplementation of glutathione precursors can restore the balance of Th1/Th2/Th17/Treg and reduce the inflammation scores of experimental colitis and Hashimoto's thyroiditis models.

• Maintaining antigen-presenting function: The level of glutathione in dendritic cells (DCS) determines their maturity and the expression of co-stimulant molecules; When glutathione is sufficient, the T-cell proliferation response induced by DC is normal; otherwise, tolerance or overactivation occurs.

3. Regulate the innate immune effect

• Macrophage polarization: High GSH promotes M2 type (anti-inflammatory, repair) polarization; Low GSH tends to be M1 type (pro-inflammatory, bactericidal), which is associated with the progression of chronic inflammatory diseases.

• NK cell activity: Clinical trials have shown that 500 mg of liposome GSH per day can increase NK cell toxic activity by approximately 25% within three months and reduce the incidence of upper respiratory tract infections.

A one-sentence summary

Glutathione, with its dual role as an "antioxidant shield + molecular switch", not only protects immune cells from being destroyed by oxidation but also adjusts the immune firepower to the "just right" position by regulating the balance of NF-κB and Th - being sufficient to kill the enemy without accidentally harming itself.

Mitochondrial and cardiovascular protection

Cardiomyocytes are rich in mitochondria but have inherently low antioxidant enzyme activity, making them highly vulnerable to ROS/RNS attacks. Glutathione is the most important "endogenous rust inhibitor" for the heart. A decrease in its level or the GSH/GSSG ratio is a common early sign of the progression of various CVD.

Atherosclerosis

• Endothelial GSH depletion → NO inactivation → vascular spasm + LDL oxidation → plaque formation.

• A decrease in GSH in macrophages activates NF-κB, amplifies the expression of adhesion molecules and inflammatory factors, and accelerates plaque inflammation.

Ischemia-reperfusion & Myocardial infarction

• At the moment of reperfusion, ROS explodes and GSH is consumed in large quantities. Supplementing GSH precursors can reduce the area of myocardial infarction by 20% to 40%.

• New mechanism: GSH protects the myocardium by blocking ferroptosis, a programmed cell death that relies on lipid peroxidation.

Heart failure

• The activity of GPx-1 in failing myocardium decreases, and lipid peroxides accumulate; Increasing GSH can improve the homeostasis and contractile functions of Ca²⁺.

• Clinical cocohort studies have shown that for every 1 μmol/L decrease in plasma GSH, the risk of ejection fraction < 40% increases by 12%

Anti-aging

Glutathione (GSH) is known as the "endogenous anti-aging center". Its core logic is: first, it blocks the three major engines of aging (oxidation, inflammation, and toxins), and then repairs the two major aging targets (mitochondria and the genome).

The aging "engine" and the braking effect of Glutathione

Oxidative stress

• After the age of 30, intracellular GSH decreases by 8-12% every ten years, and for every doubling of ROS, the telomere shortening rate increases by 30%

• GSH reduces lipid peroxides (MDA, F2-IsoPs) to harmless alcohols through GPx, blocking the free radical chain reaction.

Chronic low-grade inflammation

• GSH depletion → NF-κB/NLRP3 signal amplification → long-term increase of IL-6 and TNF-α.

• Animal experiments: Elderly mice were supplemented with 600 mg/kg·d of NAC. After 4 weeks, IL-6 in the liver and serum decreased by 42%, and TNF-α decreased by 35%.

Mitochondrial decline

• Mitochondrial GSH accounts for only 10-15% of the total, yet it determines the efficiency of the electron transport chain.

• Maintaining GSH can inhibit mtDNA mutations, reduce ROS leakage, and delay muscle atrophy and neurodegeneration.

How to evaluate glutathione

Interpretation of Indicators

Malondialdehyde (MDA)

It is the oxidation end product of the peroxidation reaction of lipids caused by free radicals in organisms, which can cause cross-linking and polymerization of macromolecules such as proteins and nucleic acids, and has cytotoxicity.

The content of malondialdehyde can reflect the rate and intensity of lipid peroxidation in the body, and indirectly reflect the degree of tissue peroxidation damage and cell damage.

MDA can accelerate the aging process, damage arterial blood vessels, damage DNA, and lead to cardiovascular diseases and cancer, etc.

8-hydroxydeoxyguanosine

8-hydroxy-2'-deoxyguanosine (8-0HdG) is a product formed when active gas radicals attack the carbon atom at the 8th position of the guanine base in DNA.

The level of 8-0HdG can reflect the oxidative damage of DNA and has become the most commonly used biomarker in DNA oxidative damage.

Glutathione peroxidase

Glutathione peroxidase (GSHPx) is an important peroxidase that is widely present in the body.

It can catalyze the transformation of GSH into GSSG, reducing toxic peroxides into non-toxic hydroxyl compounds, thereby protecting the structure and function of cell membranes from the interference and damage of peroxides.

GSHPx not only has the function of eliminating free radicals and derivatives, but also reduces the formation of lipid peroxides and enhances the body's ability to resist oxidative damage.

Glutathione S-transferase

Glutathione s-transferases (GsTs) are a group of multifunctional isoenzymes widely distributed in various organisms. They are one type of antioxidant enzymes and can exert antioxidant effects through pathways such as repairing membrane phospholipid damage caused by free radicals and inhibiting microsomal peroxidation reactions.

GSTS can catalyze the coupling of the electron-philic groups of certain endogenous or exogenous harmful substances with the thiol groups of reduced glutathione, thereby achieving the purpose of detoxification.

Glutathione

glutathione (t-GSH) is a tripeptide containing a Y-amide bond and a thiol group, which exists in almost every cell of the body.

Glutathione has antioxidant and integrated detoxification effects and serves as the hub of the entire antioxidant system. Other antioxidants such as vitamin C and E all require sufficient GSH to neutralize free radicals.

GSH can also help maintain the normal function of the immune system and contribute to the integrity of mitochondrial function.

pathway to enhance glutathione

Supplementary Premise

NAC is the abbreviation of N-acetylcysteine, which is the amino acid precursor of glutathione, an important endogenous antioxidant in the human body.

The Food and Drug Administration (FDA) of the United States approved NAC as a drug as early as 1963.

In 2022, the FDA issued guidance on the use of N-acetylcysteine (NAC) as a dietary supplement.

It is not only widely sold as a dietary supplement in many countries and regions, but also can be used as a medicine.

NAC can be directly used for the synthesis of intracellular glutathione as a precursor substance for glutathione synthesis.

Glutathione is a tripeptide composed of cysteine, glutamic acid and glycine.

After NAC is ingested, it is converted into cysteine within cells and then combines with glutamic acid and glycine to form glutathione.

Supplement directly

Oral liposomes

Glutathione may be destroyed in the gastric acid environment when taken orally, which limits its bioavailability. To overcome this challenge, researchers developed liposome glutathione.

Liposomes are tiny spherical structures composed of phospholipids that can encapsulate drugs or nutrients, protect them from being damaged by gastric acid, and help them be absorbed more effectively through the intestinal wall.

This delivery system not only enhances the stability of glutathione but also increases its availability in the body.

The uniqueness of the buccal mucosa lies in its rich vascular supply and good lymphatic drainage.

Those substances that can be absorbed by the oral and buccal mucosa enter the systemic circulation without going through the intestinal absorption mechanism, portal vein circulation or liver.

The buccal absorption surface area is approximately 200 cm ², provided by a rich vascular network. The average saliva secretion is approximately 1500 mL per day, or about 10 mL per hour, with varying amounts.

Due to its large absorption area and abundant vascular supply, the buccal mucosa is passively transported into the rich capillary circulation through cells or around cells, enabling rapid absorption of glutathione and other substances.

The supplementation of liposomal glutathione has been confirmed by research to increase the level of glutathione in the body.

Intravenous glutathione

Intravenous injection of glutathione (IV GSH) is a administration method that directly infuses high-concentration reduced GSH into the bloodstream, bypassing the gastrointestinal barrier to achieve "immediate high concentration and systemic distribution".

Batch Indications (Official instructions for China/Europe and America)

• • Drug or poison poisoning: excessive acetaminophen (paracetamol), heavy metal poisoning
• • Detoxification through radiotherapy and chemotherapy: Liver and kidney toxicity and bone marrow suppression caused by cisplatin, cyclophosphamide, etc
• • Liver disease support: alcoholic/viral hepatitis, liver cirrhosis, cholestasis during pregnancy
• • Radiation injury: Oxidative stress protection after radiotherapy or radionuclide examination

Cofactor

Vitamin C 1000 mg per day - "Regeneration Engine"

• • Mechanism: Vitamin C first "recharges" the oxidized GSSG into GSH with electrons, and at the same time, it is oxidized itself into dehydroascorbic acid. Subsequently, GSH reduces dehydroascorbic acid back to vitamin C, forming a VC ↔ GSH cycle, which increases the overall antioxidant efficiency by 2 to 3 times.
• • Evidence: Randomized double-blind trials have shown that in healthy adults with 1000 mg of VC daily for 4 consecutive weeks, the GSH content in red blood cells increased by 18%, and the oxidative stress marker 8-OHdG decreased by 25%.
• • Dosage instructions: Take it in two divided doses (500mg ×2) after meals with water to reduce gastrointestinal irritation. Reduce the dosage for patients with renal insufficiency.

Selenium 200 µg/ day - "GPx Igniter"

• Mechanism: Selenium is embedded in the active center of glutathione peroxidase (GPx) in the form of selenocysteine. Without selenium, GPx cannot catalyze GSH to clear H₂O₂ and lipid peroxides.

• Evidence: In selenium-deficient areas, after supplementing 200 µg of selenium per day for 8 weeks, the activity of whole blood GPx-1 increased by 3 to 4 times, and the delay time of LDL oxidation increased by 25%.

• Instructions for use:

- L-selenomethionine or selenium yeast has the highest bioavailability.

- When taken together with vitamin E (100-200 IU), it can synergistically inhibit lipid peroxidation.

- The upper limit is 400 µg per day. Long-term excessive intake can cause brittle nails and hair loss.

Lifestyle

High-intensity interval training (HIIT) three times a week can up-regulate NrF2-mediated GSH synthase.

Sleep for at least 7 hours and reduce exposure to alcohol and heavy metals.

References

• [1] Immunomodulatory Effects of Glutathione, Garlic Derivatives, and Hydrogen Sulfide - PMC
• [2] Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function - PMC
• [3] https://www.mjpms.in/articles/pharmaceutical-and-medicinal-properties-of-glutathione-an-overview.pdf
• [4] Sekhar RV, Patel SG, Guthikonda AP, Reid M., Balasubramanyam A., Taffet GE, Jahoor F. Insufficient synthesis of glutathione is the basis of oxidative stress in aging and can be corrected by supplementing dietary cysteine and glycine. J. Klin Nutrition. 2011; 94: 847-853. doi: 10945 /ajcn.110.003483.
• [5] Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function - PMC