Glutathione!

My awareness of the importance of glutathione in health began with the brilliant commentary on oceanic disease (IMCJ 7.1) by associate editor Sid Baker, MD.1 Since then, as I have studied detoxification, mitochondrial function, and healthy aging, the critical role of adequate glutathione to health has become ever more apparent. I have now mentioned glutathione in several previous editorials: protection from oxidative stress (IMCJ 8.3),2 protection from mercury and other toxic metals (IMCJ 8.2, 9.3, 10.4),3-5 protection from alcohol (IMCJ 11.6),6 and protection from persistent organic pollutants (POPs) (IMCJ 12.2).7 This resulted in my creating a 60-slide lecture on glutathione, which I gave for the first time at the October 2013 Restorative Medicine Conference in San Diego, California. As several attendees told me it was one of the most important lectures they had ever heard, I decided to make glutathione the topic of this editorial.

Glutathione Physiology, Production, and Recycling

Glutathione is a tripeptide (cysteine, glycine, and glutamic acid) found in surprisingly high levels—5 millimolar—concentrations in most cells. As can be seen in Figure 1, this is the same concentration in cells as glucose, potassium, and cholesterol! Considering the high level of metabolic activity required to produce glutathione, such a high level underlines its importance.

 

Glutathione exists in cells in 2 states: reduced (GSH) and oxidized (GSSG). As can be seen in Figure 2, oxidized glutathione is actually 2 reduced glutathiones bound together at the sulfur atoms.

The ratio of GSH to GSSG determines cell redox status of cells. Healthy cells at rest have a GSH/GSSG ratio >100 while the ratio drops to 1 to 10 in cells exposed to oxidant stress. Glutathione is also recognized as a thiol buffer maintaining sulfhydryl groups of many proteins in their reduced form. Glutathione is produced exclusively in the cytosol and actively pumped into mitochondria. GSH is made available in cells in 3 ways:

  1. De novo synthesis via a 2-step process catalyzed by the enzymes glutamate cysteine ligase (GCL) and glutathione synthetase (requires ATP).
  2. Regeneration of oxidized GSSG to reduced GSH by glutathione reductase (requires NADPH).
  3. Recycling of cysteine from conjugated glutathione via GGTP (requires NADPH).

Notice that all 3 require energy. The rate of synthesis, regeneration, and recycling is determined primarily by 3 factors8:

  1. De novo glutathione synthesis is primarily controlled by the cellular level of the amino acid cysteine, the availability of which is the rate-limiting step.
  2. GCL activity is in part regulated by GSH feedback inhibition.
  3. If GSH is depleted due to oxidative stress, inflammation, or exposure to xenobiotics, de novo synthesis of GSH is upregulated primarily by increasing availability of cysteine through recycling of GSSG.

These 3 methods for producing glutathione can be seen in Figure 3.

Critical Role of Glutathione in Detoxification, Inflammation, and So Much More

It is hard to overstate the importance of glutathione, key roles of which are summarized in Table 1. It plays a crucial role in shielding cellular macromolecules from endogenous and exogenous reactive oxygen and nitrogen species. While it directly quenches some free radicals, of perhaps greater importance is that it deals directly with the causes of oxidative stress such as mercury and POPs.

Glutathione is involved in the detoxification of both xenobiotic and endogenous compounds. It facilitates excretion from cells (Hg), facilitates excretion from body (POPs, Hg) and directly neutralizes (POPs, many oxidative chemicals). Glutathione facilitates the plasma membrane transport of toxins by at least 4 different mechanisms, the most important of which is formation of glutathione S-conjugates. Low levels of glutathione and/or transferase activity are also associated with chronic exposure to chemical toxins and alcohol, cadmium exposure, AIDS/HIV, macular degeneration, Parkinson’s disease, and other neurodegenerative disorders.

Glutathione directly scavenges diverse oxidants: superoxide anion, hydroxyl radical, nitric oxide, and carbon radicals. Glutathione catalytically detoxifies: hydroperoxides, peroxynitrites, and lipid peroxides.11 Another way glutathione protects cells from oxidants is through recycling of vitamins C and E as shown in Figure 4.10

Another indication of the key roles of glutathione in health is that the accumulation of GSSG due to oxidative stress is directly toxic to cells, inducing apoptosis by activation of the SAPK/MAPK pathway.12 Glutathione depletion triggers apoptosis, although it is unclear whether it is mitochondrial or cytosol pools of GSH that are the determining factor.13
Perhaps the best indicator of the importance of glutathione is that its cellular and mitochondrial levels directly are highly associated with health and longevity.

Clinical Applications

As shown in Table 2, depletion of GSH has been implicated in many chronic degenerative diseases.

GSH depletion has been strongly associated with the diseases and loss of function with aging. A representative study of community-dwelling elderly found that higher glutathione levels were associated with higher levels of physical health, fewer illnesses, and higher levels of self-rated health.15 As might be expected, then, GSH status has been found to parallel telomerase activity, an important indicator of lifespan.16 This depletion of GSH also shows up as progressive loss of mitochondrial function due to accumulation of damage to mtDNA.17 The ability of animal species to protect their mtDNA is directly proportional to longevity.18

GGT as Measure of Glutathione Need

GGT (gamma-glutamyl transferase) is upregulated in proportion to the need for glutathione such as for the detoxification of POPs.19 It provides the rate-limiting cysteine through a catabolic “salvage pathway.” Increases in GGT correlate with many diseases: metabolic syndrome, both fatal and nonfatal coronary heart disease (CHD) events, atherosclerosis, fatty liver, diabetes, cancer, hypertension, and carotid intima-media thickness.20-22 Of particular note, these are elevations of GGT within the supposedly “normal” range. For example, men with a GGT of 40 to 50 have a 20-fold increased risk of diabetes.23 Research also shows a GGT 30 to 40—well within the normal range—is associated with a doubling of the risk of all-cause mortality.24 (For a more comprehensive discussion of the remarkable correlations between GGT and disease risks, please see my editorial in IMCJ 8.3).2

Ways to Increase Intracellular Glutathione

Considering how important glutathione is to health, many researchers have looked for ways to increase intracellular and intramitochondrial levels. The good news is that there are several effective strategies. The first, of course, is to decrease the need for glutathione, which means decreasing toxic load. The most obvious is limiting alcohol consumption (see my editorial in IMCJ 11.6).6,25 Less obvious is decreasing exposure to POPs, the primary source of which are conventionally grown foods. (See my editorial in
IMCJ 12.2.)7 Another strategy is to provide other antioxidants to decrease oxidative stress. A good example is α-lipoic acid, supplementation of which increases mitochondrial glutathione levels even though ALA is not used in the synthesis or recycling of glutathione.26

The obvious strategy is to directly administer glutathione. This can be done orally, topically, intravenously, intranasally, or in nebulized form.

Clinical Application

Direct administration and promotion of production of glutathione have been used effectively in a wide range of diseases: Parkinson’s, peripheral obstructive arterial disease, cystic fibrosis, emphysema, COPD, preterm infants autism, contrast-induced nephropathy, chronic otitis media, lead exposure, nail biting(!), nonalcoholic fatty liver disease, exercise-induced fatigue—the list is long and surprisingly diverse.36-46

Summary

Clearly, adequate availability of glutathione is critical for maintaining health, protecting the body from toxins, and promoting longevity. Fortunately, there is much we can do to optimize glutathione levels: primarily decrease toxin exposure (including alcohol) and promote production with regular consumption of whey or NAC. I think we are just scratching the surface of the clinical benefits that can be achieved through enhancing intracellular and intramitochondrial glutathione. (I hope you, my dear reader, enjoy these editorials as much as do in writing them.)

Joseph Pizzorno, ND, Editor in Chief
drpizzorno@innovisionhm.com

 

References

  1. MacDonald Baker S. The metaphor of oceanic disease. Integrative Med Clin J. 2008;7(1):40-45.
  2. Pizzorno J. The path ahead: measuring oxidative stress. Integrative Med Clin J. 2009;8(3):8-10.
  3. Pizzorno J. The path ahead: is mercury toxicity an epidemic? (Part II). Integrative Med Clin J. 2009;8(2):8-12.
  4. Pizzorno J. The path ahead: vitamin D: still learning about dosage. Integrative Med Clin J. 2010;9(3):8-11.
  5. Pizzorno J. The path ahead: clinical experience in decreasing mercury load. Integrative Med Clin J. 2011;10(4):10-13.
  6. Pizzorno J. The path ahead: what should we tell our patients about alcohol? Integrative Med Clin J. 2012;11(6):8-11.
  7. Pizzorno J. The path ahead: persistent organic pollutants (POPs)—a serious clinical concern. Integrative Med Clin J. 2013;12(2):8-11.
  8. Biswas SK, Rahman I. Environmental toxicity, redox signaling and lung inflammation: the role of glutathione. Mol Aspects Med. 2009;30(1-2):60-76.
  9. Hall MN, Niedzwiecki M, Liu X, et al. Chronic arsenic exposure and blood glutathione and glutathione disulfide concentrations in bangladeshi adults. Environ Health Perspect. 2013;121(9):1068-1074.
  10. Teixeira FK, Menezes-Benavente L, Galvão VC, Margis-Pinheiro M. Multigene families encode the major enzymes of antioxidant metabolism in Eucalyptus grandis L. Genet Mol Biol. 2005;28(3):529-538.
  11. Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685-2700. doi: 10.1089/ARS.2009.2695.
  12. Filomeni G, Aquilano K, Civitareale, et al. Activation of c-Jun-N-terminal kinase is required for apoptosis triggered by glutathione disulfide in neuroblastoma cells. Free Radic Biol Med. 2005;39(3):345-354.
  13. Marí Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal. 2009;11(11):2685-2700. doi: 10.1089/ARS.2009.2695.
  14. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191-214.
  15. Julius M, Lang CA, Gleiberman L, Harburg E, DiFranceisco W, Schork A. Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol. 1994;47(9):1021-1026.
  16. Borrás C, Esteve JM, Viña JR, Sastre J, Viña J, Pallardó FV. Glutathione regulates telomerase activity in 3T3 fibroblasts. J Biol Chem. 2004;279(33):34332-34335.
  17. Wei YH, Ma YS, Lee HC, Lee CF, Lu CY. Mitochondrial theory of aging matures—roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei). 2001;64(5):259-270.
  18. Barja G, Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J. 2000;14(2):312-318.
  19. Pompella A, Emdin M, Franzini M, Paolicchi A. Serum gamma-glutamyltransferase: linking together environmental pollution, redox equilibria and progression of atherosclerosis? Clin Chem Lab Med. 2009;47(12):1583-1584.
  20. Jo SK, Lee WY, Rhee EJ, et al. Serum gamma-glutamyl transferase activity predicts future development of metabolic syndrome defined by 2 different criteria. Clin Chim Acta. 2009;403(1-2):234-240.
  21. Van Hemelrijck M, Jassem W, Walldius G, et al. Gamma-glutamyltransferase and risk of cancer in a cohort of 545,460 persons – the Swedish AMORIS study. Eur J Cancer. 2011;47(13):2033-2041.
  22. Eroglu S, Sade LE, Polat E, Bozbas H, Ulus T, Muderrisoglu H. Association between serum gamma glutamyltransferase activity and carotid intima-media thickness. Angiology. 2011;62(2):107-110.
  23. Jo SK, Lee WY, Rhee EJ, et al. Serum gamma-glutamyl transferase activity predicts future development of metabolic syndrome defined by 2 different criteria. Clin Chim Acta. 2009;403(1-2):234-240.
  24. Van Hemelrijck M, Jassem W, Walldius G, et al. Gamma-glutamyltransferase and risk of cancer in a cohort of 545,460 persons – the Swedish AMORIS study. Eur J Cancer. 2011;47(13):2033-2041.
  25. Eroglu S, Sade LE, Polat E, Bozbas H, Ulus T, Muderrisoglu H. Association between serum gamma-glutamyltransferase activity and carotid intima-media thickness. Angiology. 2011;62(2):107-110.
  26. M, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999;13(2):411-418.
  27. Buhl R, Vogelmeier C, Critenden M, et al. Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol. Proc NatlAcad Sci U S A. 1990;87(11):4063-4067.
  28. Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med. 2011;17(9):827-833.
  29. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011;17(12):CR677-CR682.
  30. Pendyala L, Creaven PJ. Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial. Cancer Epidemiol Biomarkers Prev. 1995;4(3):245-251.
  31. Liber CS, Packer L. S-Adenosylmethionine: molecular, biological, and clinical aspects—an introduction. Am J Clin Nutr. 2002:76(5):1148S-1150S.
  32. Pamuk GE, Sonsuz A. N-acetylcysteine in the treatment of non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2003;18(10):1220-1221.
  33. Martínez Alvarez JR, Bellés VV, López-Jaén AB, Marín AV, Codoñer-Franch P. Effects of alcohol-free beer on lipid profile and parameters of oxidative stress and inflammation in elderly women. Nutrition. 2009;25(2):182-187.
  34. Li N, Jia X, Chen CY, et al. Almond consumption reduces oxidative DNA damage and lipid peroxidation in male smokers. J Nutr. 2007;137(12):2717-2722.
  35. Sharma H, Datta P, Singh A, et al. Gene expression profiling in practitioners of Sudarshan Kriya. J Psychosom Res. 2008;64(2):213-218.
  36. Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D. Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson’s disease. Mov Disord. 2009;24(7):979-983.
  37. Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2002;77(8):754-759.
  38. Bishop C, Hudson VM, Hilton SC, Wilde C. A pilot study of the effect of inhaled buffered reduced glutathione on the clinical status of patients with cystic fibrosis. Chest. 2005;127(1):308-317.
  39. Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009;136(2):381-386.
  40. Cooke RW, Drury JA. Reduction of oxidative stress marker in lung fluid of preterm infants after administration of intra-tracheal liposomal glutathione. Biol Neonate. 2005;87(3):178-180.
  41. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011;17(12):CR677-CR682.
  42. Saitoh T, Satoh H, Nobuhara M, et al. Intravenous glutathione prevents renal oxidative stress after coronary angiography more effectively than oral N-acetylcysteine. Heart Vessels. 2011;26(5):465-472.
  43. Testa B, Testa D, Mesolella M, D’Errico G, Tricarico D, Motta G. Management of chronic otitis media with effusion: the role of glutathione. Laryngoscope. 2001;111(8):1486-1489.
  44. Kasperczyk S, Dobrakowski M, Kasperczyk A, Ostałowska A, Birkner E. The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead. Clin Toxicol (Phila). 2013;51(6):480-486.
  45. Ghanizadeh A, Derakhshan N, Berk M. N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial. Antiinflamm Antiallergy Agents Med Chem. 2013;12(3):223-228.
  46. Medved I, Brown MJ, Bjorksten AR, et al. N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J Appl Physiol. 2004;97(4):1477-1485
  47. Price-Pottenger Nutrition Foundation. Pottenger Cat Studies [DVD]. Lemon Grove, CA: PPNF.

Leave a Reply

Your email address will not be published. Required fields are marked *