Glutathione (GSH)
Endogenous Antioxidants

Author: Gianpiero Pescarmona
Date: 14/09/2009


Glutathione (GSH) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.
GSH Nebraska: general info + transporters

Comprehensive reviews

The Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures?2017

Tissue distribution and concentration

2-5 mM according to the tissue (5 mM = 1,5366 mg/ml)


GSH half life

It ranges from 3/5 hours to 30/50 hours

If we assume 40kg tissues with an average 2.5 mM GSH (ca 750 mg/l) it means 30 g GSH in the whole body with an half-life of 48hours its life is around 10 days. 3 g. GSH a 1.5 g. glutamate a day.

dietary Glutamate

Glutamate is produced in the human body and plays an essential role in metabolism.
Almost two kilograms (about four pounds) of naturally occurring glutamate are found in muscles, in the brain, in kidneys, in the liver and in other organs and tissues.

The monosodium glutamate added to foods to improve taste represents only a small amount of the total glutamate present in most foods. For example, the average daily amount of glutamate consumed in bound form as protein from food is about 15 grams. In addition, about 1 gram of free glutamate in food would also be consumed during the same day. In contrast, average daily intake of added monosodium glutamate ranges between 0.5 grams and 3.0 grams a day, dependent upon local dietary customs and cuisine.
h4. Glutamine for Purine biosynthesis

400/800 mg day uric acid

Endogenous Glutathione Conjugates: Occurrence and Biological Functions, 1996

GSH synthesis

GS amino acid transport

Inviato da iPad

Cellular GSH homeostasis and GSH-dependent reactions. Intracellular GSH balance is maintained by de novo synthesis, regeneration from GSSG, and extracellular GSH uptake. In transport epithelial cells, such as enterocytes, γ -glutamyl transferase ( γ -GT) and dipeptidase (DP) catalyzed the hydrolysis of extracellular GSH to its constituent amino acids, glutamate, cysteine and glycine. Additionally, intestinal epithelial cells can import intact GSH from the lumen via specifi c plasma membrane transporters. Cytosolic synthesis of GSH takes place in two ATP-dependent reactions catalyzed by glutamate-cysteine ligase (GCL) and glutathione synthase (GS). The intracellular GSH pool, present in millimolar concentrations, is involved in various GSH-dependent reactions. Compartmentation of GSH within the mitochondria, nucleus or endoplasmic reticulum creates distinct and independently regulated subcellular redox pools. As part of the antioxidant defence system, GSH participates in conjugation reactions catalyzed by glutathione-S-transferases (GSTs), in the reduction of hydrogen peroxide (H O ) and lipid hydroperoxides (LOOH) catalyzed by glutathione peroxidases (Gpxs), and the reduction 2 2 of protein-disulfi des (PrSSG) catalyzed by glutaredoxins (Grxs). The reduction of glutathione disulfi de (GSSG) by glutathione reductase (GR) in the GSH redox cycle regenerates GSH. GSSG reduction occurs at the expense of NADPH, produced from the pentose phosphate pathway (PPP) from glucose oxidation.

GSH regulation! gsh+glucocorticoids

GSH functions

Glutathione exists in reduced (GSH) and oxidized states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent (H++ e-) to other unstable molecules, such as reactive oxygen species. In donating an electron, glutathione itself becomes reactive, but readily reacts with another reactive glutathione to form glutathione disulfide (GSSG).
Such a reaction is possible due to the relatively high concentration of glutathione in cells (up to 5 mM in the liver ).
GSH can be regenerated from GSSG by the enzyme glutathione reductase.

Peroxides reduction

Protein SS groups reduction and Protein/GSH adducts cleavage


GSSG cholesterol synthesis

cholesterol synthesis and GSSG


Glutathionylation: a regulatory role of glutathione in physiological processes, 2018

Direct and indirect regulatory roles in physiological processes include glutathionylation of:

  • major transcriptional factors,
  • eicosanoids,
  • cytokines,
  • nitric oxide (NO)

Which is the information content of GSH molecule?

GSH and Aging


  • Abstract Text:
    DESCRIPTION (Adapted from the Applicant's Abstract): Glutathione (GSH) is a major antioxidant present in high concentrations in nearly all living cells, with numerous critical functions in cellular homeostasis and defense. The investigator's previous results and those of others suggest that GSH depletion is a general phenomenon of aging tissues and organisms. They hypothesize that the loss of GSH is caused by an impairment in its biosynthesis and represents a key factor in the biological aging process, based upon its essential roles. While considerable data have been accumulated to support the important role for GSH in aging, little information is available regarding the mechanisms responsible for its depletion during aging. The overall goals of the present research proposal are to determine the cause of the GSH deficiency in the aging mouse and to elucidate the mechanisms by which caloric restriction (CR) increases GSH and prevents the aging-deficiency. To this end, they will determine the effects of aging and CR on the metabolism of Met, Cys and GSH in the C57BL/6 mouse model. In addition, they will also examine the effects of specific enhancement and depletion of GSH on longevity, using lifelong feeding with GSH monoethyl ester and buthionine sulfoximine, respectively. A systematic and multi-level approach will be used to assess metabolism. The specific activities of the enzymes involved in GSH, Cys and Met metabolism will be determined along with the levels of specific intermediate metabolites in different tissues. GSH turnover will be assessed on whole animals by injection of radiolabeled precursors. Animals of 4 age groups will be analyzed in order to assess growth and developmental changes as well as aging-specific changes. The results of these studies will provide new information on the biochemical mechanisms of the aging process, which will be important in the development of strategies to enhance health and longevity.

caloric restriction GSH

Curcumin increases total GSH and GSH/GSSG ratio

Liquiritigenin, a flavonoid aglycone from licorice, has a choleretic effect and the ability to induce hepatic transporters and phase-II enzymes. 2009

GSH and NO


Vitamin D and GSH


NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats. 2021

Using biochemical assays, other investigations determined that NAC and active vitamin D increase GSH.

Vitamin D and Acute Kidney Injury: A Two-Way Causality Relation and a Predictive, Prognostic, and Therapeutic Role of Vitamin D. 2021

Also, VitD acted as an antioxidant factor by increasing GSH.

Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice. 2019

These results suggest that GSH may have a direct effect on VD metabolism.

GSH and cathecol estrogens

2022-04-07T22:16:06 - Gianpiero Pescarmona

geranylgeranyl glutathione

geranylgeranyl glutathione

S-Geranylgeranyl-L-glutathione is a ligand for human B cell-confinement receptor P2RY8. 2019

Using a seven-step biochemical fractionation procedure and a drop-out mass spectrometry approach, we show that a previously undescribed biomolecule, S-geranylgeranyl-L-glutathione (GGG), is a potent P2RY8 ligand that is detectable in lymphoid tissues at the nanomolar level.

Proteins geranylgeranylation

2022-04-05T15:07:47 - Gianpiero Pescarmona

GSH and Calcium

Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives, 2022

Abstract: Extracellular glutathione (GSH) and oxidized glutathione (GSSG) can modulate the function of the extracellular calcium sensing receptor (CaSR). The CaSR has a binding pocket in the extracellular domain of CaSR large enough to bind either GSH or GSSG, as well as the naturally occurring oxidized derivative L-cysteine glutathione disulfide (CySSG) and the compound cysteinyl glutathione (CysGSH). Modeling the binding energies (∆G) of CySSG and CysGSH to CaSR reveals that both cysteine derivatives may have greater affinities for CaSR than either GSH or GSSG. GSH, CySSG, and GSSG are found in circulation in mammals and, among the three, CySSG is more affected by HIV/AIDs and aging than either GSH or GSSG. The beta-carbon linkage of cysteine in CysGSH may model a new class of calcimimetics, exemplified by etelcalcetide. Circulating glutathionergic compounds, particularly CySSG, may mediate calcium-regulatory responses via receptor-binding to CaSR in a variety of organs, including parathyroids, kidneys, and bones. Receptor-mediated actions of glutathionergics may thus complement their roles in redox regulation and detoxification. The glutathionergic binding site(s) on CaSR are suggested to be a target for development of drugs that can be used in treating kidney and other diseases whose mechanisms involve CaSR dysregulation.

2020-08-20T14:33:53 - Gianpiero Pescarmona

glycine and overweight

Integration of Traditional and Metabolomics Biomarkers Identifies Prognostic Metabolites for Predicting Responsiveness to Nutritional Intervention against Oxidative Stress and Inflammation, 2017

2011-12-15T14:32:42 - chiara brusa


Might low GSH levels have a role in Churg-Strauss syndrome (CSS) onset?

GSH is involved in cysteinylleukotrienes (CysLTs) synthesis but not in leukotriene B4 (LTB4) synthesis.

Low GSH levels might cause a decrease in CysLTs production thus eliciting imbalance between CysLTs receptors (CysLTRs) and LTB4 receptors (LTBRs) stimulation.

Imbalance between CysLTRs and LTBRs stimulation is one of the three theories formulated to explain the relationship between CysLTs antagonists and CSS onset.

Low GSH levels might have the same influence of CysLTs antagonists in CSS onset.

2009-09-14T16:23:31 - Gianpiero Pescarmona



Di seguito una mia osservazione su uno studio del passato che viene spesso citato come prova del deficit e dell’efficacia dell’integrazione:

Il lavoro pubblicato su PNAS (Proc. Natl. Acad. Sci. USAVol. 94, pp. 1967–1972, March 1997 Glutathione deficiency is associated with impaired survival in HIV disease LEONORE A. HERZENBERG*, STEPHEN C. DE ROSA*†, J.GREGSON DUBS*, MARIO ROEDERER*, MICHAEL T. ANDERSON*, STEPHEN W. ELA*, STANLEY C. DERESINSKI‡, AND LEONARD A. HERZENBERG*), presenta il fianco a diverse critiche.

Non è dimostrativo, per stessa ammissione degli autori, nonostante il titolo lasci intendere che lo è (“no conclusion can be drawn until NAC is administered in a properly controlled prospective trial with survival as the primary end-point”) e presenta molti difetti, a mio parere:

1) periodo di osservazione di due anni, ma la terapia è solo di 2-8 mesi,

2) numero di casi limitato,

3) inclusione di soggetti con terapia antiretrovirale e soggetti senza negli stessi gruppi,

4) mancata menzione di droghe diverse dall’alcool nei soggetti in studio,

5) grande dispersione di valori riguardanti il Glutathione: almeno il 50% di sieronegativi asintomatici – non trattati con NAC – ha gli stessi valori di glutathione del 50% di sieronegativi sani di controllo. Questo prima e dopo il trattamento (vedi fig. 5),

6) del gruppo trattati, che denuncia una diminuita mortalità, non è precisato se decessi o malattie siano avvenuti solo tra quelli che non hanno riscontrato un aumento di glutathione nonostante la terapia,

7) la stessa domanda può essere fatta riguardo i soggetti non trattati,

8) molti soggetti trattati con alte dosi di glutathione non hanno mostrato alterazioni della sua concentrazione,

9) se ho capito bene, il follow up a due anni è stato fatto dopo l’interruzione dello studio durato 8 settimane, e la continuazione dell’assunzione di NAC è avvenuta solo per alcuni, con una mediana di 24 settimane totali (con range piuttosto ampio: 8-32). E’ stata scelta la mediana perché la media sarebbe stata molto inferiore alla mediana?!

10) è stato studiato l’effetto sulla mortalità di un trattamento somministrato per una piccola frazione dei due anni di osservazione (meno di ¼)! Ha poco senso.

In conclusione, lo studio mi pare totalmente invalido e l’ipotesi, pur interessante, non mi convince, poiché posso osservare che molti soggetti sani sieronegativi hanno “poco” glutathione, mentre molti soggetti sieropositivi immunodepressi ne hanno “molto”.

Tentativi farmacologici per aumentare il GSH

Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS. 1995

The systemic availability of oral glutathione.1992

N-acetylcysteine replenishes glutathione in HIV infection.2000

Glutathione deficiency is associated with impaired survival in HIV disease.1997

Practicalities of glutathione supplementation in nutritional support.2002

Intracellular glutathione in the peripheral blood cells of HIV-infected patients: failure to show a deficiency.1996

AddThis Social Bookmark Button