by: Steve Haltiwanger, MD, CCN

Introduction:

Glutathione is the master antioxidant of the body. Glutathione, which is composed of three amino acids (cysteine, glycine and glutamic acid), is present in high concentration both in the bloodstream and inside of cells. When combined together in this form, these amino acids provide the cells with an essential compound that is a critical part of the body’s natural defense system (Lomaestro et al., 1995). Glutathione has to be continually manufactured because it is constantly being utilized to protect the cells of the body.

Glutathione is an important cellular antioxidant that protects cells against oxidative stress, and it has a critical role in cellular detoxification. Glutathione along with ascorbic acid, the major dietary water-soluble antioxidant, plays a central role in the regulation of the oxidation state inside of cells (Meister, 1994). A reduction in glutathione levels in the bloodstream and in the cells has been implicated in numerous diseases. In addition, thousands of medical articles show evidence that therapies that renormalize glutathione levels are beneficial in these same conditions.

Blood glutathione levels have been identified as being one of the most important indicators of overall health.  As the master antioxidant in the body glutathione has a range of diverse metabolic functions including acting as a free radical scavenger, “recharging” depleted antioxidants back into their active state (Vitamin C, Vitamin E, Vitamin A, etc.), maintaining the immune system, supporting protein structures, promoting amino acid uptake by cells, synthesis and repair of DNA, detoxifying drugs and chemical toxins, and removing heavy metals such as mercury (Fraternale et al., 2006). “It is known that GSH is not transported to most cells and tissues in a free form (Fraternale et al., 2006).”

The present methodologies for elevating glutathione levels include oral supplementation of glutathione, oral supplementation of the amino acid glutathione precursors, use of nutritive substances that support enzymatic glutathione production and injection of glutathione.  Each of these methods has severe draw backs.  For example, it is known that glutathione is destroyed by stomach acids making oral supplementation ineffective.  While oral supplementation of amino acid precursors and glutathione enzyme cofactors does often show elevated levels of blood glutathione levels by 10-40% after four weeks of use; these results are unpredictable and they are time- and dose-dependent. These supplements include: whey protein, selenium, lipoic acid, NAC, glutamine, glycine, vitamin C, and Vitamin E. However the effectiveness of supplements to improve glutathione levels is dependent upon many factors including patient compliance, age, level of exposure to environmental toxins and the need to ingest the supplements multiple times during the day in order to maintain adequate glutathione levels.

Many Drugs Deplete Glutathione:

The medical literature contains thousands of articles about how different chemicals and drugs deplete glutathione levels in the body. This section will review several representative examples.

  • Paracetamol is the name of an analgesic agent that is widely used as an over the counter pain medication in countries around the world. In the USA the drug is known as acetaminophen. In 1993 it was reported that 200–300 deaths occurred every year from paracetamol poisoning in the UK (Spooner, 1993). In the USA overdoses of prescription and nonprescription drugs containing acetaminophen results in more calls to poison control centers in the US than do overdoses of any other medication, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, and 458 deaths due to acute liver failure per year (Lee, 2004).  A report on the cases acute liver failure by the CDC between 2000 and 2004 determined that acetaminophen toxicity was the cause in 41% of adult cases of liver failure (Bower et al., 2007).
  • Acetaminophen (APAP) hepatotoxicity is currently the single most important cause of acute liver failure in the US, and is associated with a significant number of deaths (Liu et al., 2006).”
  • The reason for the deaths from acute liver failure after acetaminophen overdose results from acute depletion of liver glutathione levels. Glutathione is a critical antioxidant molecule involved in the detoxification of acetaminophen/paracetamol in the liver. If a person does not receive immediate treatment with glutathione producing substances, the liver will fail and then the only other treatment is a liver transplant.
  • The acute treatment of poisoning with this analgesic involves using antidotes such as intravenous infusions of N-acetylcysteine or alpha-lipoic acid, which are nutrients used by the body to produce glutathione (Norman et al., 2001). In 1977, Dr. Burton M. Berkson also discovered that alpha-lipoic acid, which generates glutathione production in the liver, could also save the livers of individuals suffering from mushroom poisoning (Berkson, 1979)
  • Mild cases of liver toxicity are often treated with oral doses of N-acetylcysteine, alpha-lipoic acid or the essential amino acid methionine, which serve as substrates for glutathione synthesis. In addition, the use glutathione promoting compounds like alpha-lipoic acid along with silymarin and selenium can be beneficial in some individuals suffering from viral hepatitis because of their ability to regenerate antioxidants and protect the liver from free-radical damage (Berkson, 1999).
  • The problem of liver dysfunction with use of analgesics is wide-spread and is not limited just to individuals who take drug over doses. Millions of people suffer from chronic pain just in the USA. It is a common medical policy for doctors to tell their patients to take acetaminophen containing analgesics with a typical dose being two tablets or capsules four times a day. Unfortunately, one-third of individuals who use 4 grams of acetaminophen daily may have an increase in their liver function tests to three times their normal value (Watkins et al., 2006). Some clinicians believe that such chronic use of acetaminophen containing medications can cause chronic liver failure.
  • Drugs commonly used in anesthesia practice may create oxidative stress and glutathione depletion in peripheral T cells. “This mechanism could contribute to the immune suppression that occurs transiently in the early postoperative period (Delogu et al., 2004).” This type of research supports the need to support glutathione levels in individuals who are undergoing surgical procedures where anesthetic agents are used. In addition, maintaining glutathione levels in individuals who are recovering from injuries and surgery is beneficial because of the positive response that glutathione has on wound healing (Kopal et al., 2007).

Immune System and Glutathione:

  • The immune system requires glutathione to function
  • When glutathione is depleted immune system function declines
  • Infections of all types cause glutathione depletion
  • The immune system works best if the lymphoid cells have adequate levels of glutathione. Even small reductions in the intracellular glutathione level have profound effects on lymphocyte and immune functions.
  • Glutathione is involved in T-cell activation low glutathione could affect the outcome of the immune response during systemic diseases and aging (Kim, 2007).
  • “Glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness (Robinson et al., 1993).”
  • Infection and trauma produce inflammatory stress in the body (Grimble, 1997). When inflammation is prolonged tissue damage, enhanced inflammatory mediator production and suppressed lymphocyte function may occur as a consequence.
  • In addition, chronic inflammation predisposes susceptible cells to undergo cancerous transformation. In general, the longer the inflammation persists, the higher the risk of cancer. Inflammatory processes may induce DNA mutations in cells via oxidative stress. DNA mutation and mitochondrial dysfunction occurs when the generation of free radicals in a system exceeds the system’s antioxidant protection (Federico et al., 2007).
  • “In sepsis, a state of severe oxidative stress is encountered; with host endogenous antioxidant defenses overcome (Macdonald et al., 2003).”
  • “Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration (Fläring et al., 2003).”
  • Certain cellular functions, such as DNA synthesis are disrupted by oxidative stress; however DNA synthesis is favored by high levels of the antioxidant glutathione (Dröge et al., 2000).

Glutathione and Cancer:

  • Glutathione may be beneficial in cancer therapies
  • Some oncologists recommend that patients undergoing chemotherapy and/or radiation therapy should not use supplemental antioxidants and other nutrients. The concern that these oncologist’s have is that use of antioxidants might interfere with radiation and some chemotherapies. “This is despite the common use of amifostine and dexrazoxane, 2 prescription antioxidants, during chemotherapy and/or radiation therapy (Simone et al., 2007).”
  • “The MEDLINE and CANCERLIT databases were searched from 1965 to November 2003 using the words vitamins, antioxidants, chemotherapy, and radiation therapy. Bibliographies of articles were searched. All studies reporting concomitant nutrient use with chemotherapy and/or radiation therapy (280 peer-reviewed articles including 62 in vitro and 218 in vivo) were indiscriminately included. RESULTS: Fifty human clinical randomized or observational trials have been conducted, involving 8,521 patients using beta-carotene; vitamins A, C, and E; selenium; cysteine; B vitamins; vitamin D3; vitamin K3; and glutathione as single agents or in combination. CONCLUSIONS: Since the 1970s, 280 peer-reviewed in vitro and in vivo studies, including 50 human studies involving 8,521 patients, 5,081 of whom were given nutrients, have consistently shown that do not interfere with therapeutic modalities for cancer. Furthermore, non-prescription antioxidants and other nutrients enhance the killing of therapeutic modalities for cancer, decrease their side effects, and protect normal tissue. In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival (Simone et al., 2007).”
  • Glutathione treatment has been shown to be an effective in reducing toxicity and side effects in individuals with ovarian cancer who are treated with cisplatin chemotherapy. “Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping (Smyth et al., 1997).”
  • “Application of Cisplatin and Glutathione seems to be safe and feasible and the antitumoral efficacy of cisplatin is apparently not impaired by the concomitant use of Glutathione in patients with solid tumors (Schmidinger et al., 2000).”
  • Many individuals will develop neurological symptoms when given chemotherapy agents. Some studies have shown that chemotherapy agents lower glutathione levels in brain tissue and that the use of glutathione can reduce brain toxicity (Cascinu et al., 2002).

Some examples of Clinical Conditions Involving or Responsive to Glutathione:

  • Chronic diseases
  • Pulmonary disease
  • Degenerative brain conditions
  • HIV infection
  • Acute pancreatitis
  • Burn injuries
  • Cancer
  • Viral Infections
  • Immune dysfunctions
  • Diabetes
  • Rheumatoid arthritis and systemic lupus erythematosus
  • Osteoarthritis
  • Strokes and heart attacks
  • One of the most amazing things that was discovered in this review of glutathione was – that individuals with all types of chronic illnesses characteristically have low glutathione levels (Kharb et al., 2000). Many researchers have now determined that the ability to maintain high levels of glutathione in the body is one of the strongest indicators of good health. “The conclusion is that a decrease in GSH is a risk factor for chronic diseases that may be used to monitor the severity and progress of the diseases (Lang et al., 2000).”
  • An imbalance in oxidant/antioxidant levels in the cells and tissues is a major cause of cell damage and is the hallmark for lung inflammation. Glutathione is a vital protective antioxidant, which plays a key role in the control of inflammatory processes in the lungs (Rahman, 2005). Oxidative stress is an important feature in the causation of chronic obstructive pulmonary disease. Controlling oxidative stress with antioxidants or boosting the endogenous levels of antioxidants such as glutathione is likely to be beneficial in the treatment of COPD (Rahman, 2006).
  • Detrimental changes occur in the brain and nervous system when oxidative stress overwhelms the oxidative defense systems, such as glutathione (Reynolds et al., 2007). In the central nervous system glutathione protects against reactive oxygen species , infections and toxic substances. Conditions that result in marked reductions of glutathione levels inside of brain cells and mitochondria are associated with cell death (Cooper et al., 1997).
  • Blood levels of glutathione are typically low in individuals with HIV infections (Delmas-Beauvieux et al., 1996; Look et al., 1997). “Neuronal damage in HIV infection results mainly from chronic activation of brain tissue and involves inflammation, oxidative stress, and glutamate-related neurotoxicity. Glutamate toxicity acts via two distinct pathways: an excitotoxic one, in which glutamate receptors are hyperactivated, and an oxidative one, in which cystine uptake is inhibited, resulting in glutathione depletion, oxidative stress, and cell degeneration (Gras et al., 2006).”
  • Numerous studies have shown that HIV patients who receive treatments that raise glutathione levels have less medical complications.
  •  “The role of oxidative stress in acute pancreatitis has been evidenced indirectly by beneficial effects of antioxidants as well as directly by pancreatic glutathione depletion and increased lipid peroxidation (Gómez-Cambronero et al., 2002).”
  • In burn patients increased free radical production is paralleled by impaired antioxidant mechanisms; as indicated by burn-related decreases in superoxide dismutase, catalase, glutathione, alpha tocopherol, and ascorbic acid levels. “These data collectively support the hypothesis that cellular oxidative stress is a critical step in burn-mediated injury, and suggest that antioxidant strategies designed to either inhibit free radical formation or to scavage free radicals may provide organ protection in patients with burn injury (Horton, 2003).”
  • “Decreased glutathione levels have been found in numerous diseases such as cancer, viral infections, and immune dysfunctions (Fraternale et al., 2006).”
  • “Antioxidant molecules, such as GSH can inhibit viral replication (Fraternale et al., 2006).”
  • Glutathione levels are typically lower in both Type I and Type II diabetics (Ozdemir et al., 2005; Likidlidlid et al., 2007). “Analyses of whole blood GSH showed that GSH was significantly lower in diabetic cases compared to the other groups (Samiec et al., 1998).”
  • Rheumatoid arthritis and systemic lupus erythematosus are two chronic inflammatory conditions which have been associated with low levels of serum and erythrocyte glutathione when compared to normal (Fidelus et al., 1987).
  • Glutathione levels as measured by erythrocyte glutathione are low in the blood of individuals with osteoarthritis (Surapaneni et al., 2007).
  • Acute strokes and acute myocardial infarctions create severe oxidative stress on the body. The body will initially respond adaptively by increasing the production of antioxidant enzymes like glutathione in order to protect and preserve surviving tissues (Zimmermann et al., 2004). This places severe demands on the production of antioxidants like glutathione. If and when the demands overwhelm the production of endogenous antioxidants like glutathione, antioxidant levels including glutathione levels fall and tissue damage becomes more severe. This is particularly critical in the first week following an ischemic event when antioxidant enzyme concentrations are decreased below normal levels (Cherubini et al., 2000; Demirkaya et al., 2001). Maintaining adequate levels of antioxidants in individuals with vascular disease and in individuals who have ischemic events can help reduce medical complications. Although acceptance of the need for aggressive antioxidant support is not universally accepted in mainstream medicine many clinicians and researchers have found that approaches that prevent exhaustion of antioxidant levels like glutathione in both acute and chronic medical conditions are very beneficial (Berger et al., 2007).

References:

  1. Aebi S, Assereto R, Lauterburg BH. High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in plasma and urine. Eur J Clin Invest. 1991 Feb;21(1):103-10.
  2. Arosio E, De marchi S, Zannoni M, et al. Effect of Glutathione Infusion on Leg Arterial Circulation, Cutaneous Mircocirculation, and Pain-Free Walking Distance in Patients With Peripheral Obstructive Arterial Disease. A Randomized, Double-Blind, Placebo-Controlled Trial, Mayo Clin Proc. 2002;77:754-759.
  3. Atalay M, Sen CK. Physical exercise and antioxidant defenses in the heart. Ann N Y Acad Sci. 1999 Jun 30;874:169-77.
  4. Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and physical exercise. Cell Biochem. 2003 Nov;253(1-2):307-12.
  5. Baynes J, Dominiczak MH. Medical Biochemistry. New York, NY: Mosby, 1999.
  6. Berger MM, Chioléro RL. Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Crit Care Med. 2007 Sep;35(9 Suppl):S584-90.
  7. Berkson B. Thioctic acid in treatment of hepatotoxic mushroom poisoning. New England Journal of Medicine. 1979;300:371
  8. Berkson BM. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin (Munich).  1999 Oct 15;94 Suppl 3:84-9.
  9. Bridgeman MME, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46:39–42.
  10. Bower WA, Johns M, Margolis HS, et al. Population-Based Surveillance for Acute Liver Failure. Am. J. Gastroenterol. June 29, 2007.
  11. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med. 2003 Apr 1;34(7):928-36.
  12. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective Effect Of Reduced Glutathione On Oxaliplatin-Based Chemotherapy In Advanced Colorectal Cancer: A Randomized Double-Blind, Placebo-Controlled Trial. Jour. Clin. Oncol. 2002;20(16); 3478-83.
  13. Chang CK, Huang HY, Tseng HF, Hsuuw YD, Tso TK. Interaction of vitamin E and exercise training on oxidative stress and antioxidant enzyme activities in rat skeletal muscles. J Nutr Biochem. 2006 Apr 25; [Epub ahead of print].
  14. Cherubini A, Polidori MC, Bregnocchi M, et al. Antioxidant profile and early outcome in stroke patients. Stroke. 2000 Oct;31(10):2295-300.
  15. Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G. Neuroprotective strategies in Parkinson’s disease: protection against progressive nigral damage induced by free radicals. Neurotox Res. 2000;2(2-3):293-310.
  16. Ciuchi E, Odetti P, Prando R. The effect of acute glutathione treatment on sorbitol level in erythrocytes from diabetic patients. Diabetes Metab. 1997 Feb;23(1):58-60.
  17. Cooper AJ, Kristal BS. Multiple roles of glutathione in the central nervous system. Biol Chem. 1997 Aug;378(8):793-802.
  18. Delmas-Beauvieux MC, Peuchant E, Couchouron A, et al. The enzymatic antioxidant system in blood and glutathione status in human immunodeficiency virus (HIV)-infected patients: effects of supplementation with selenium or beta-carotene. Am J Clin Nutr. 1996 Jul;64(1):101-7.
  19. Delogu G, Antonucci A, Moretti S, et al.  Oxidative stress and mitochondrial glutathione in human lymphocytes exposed to clinically relevant anesthetic drug concentrations. J Clin Anesth. 2004 May;16(3):189-94.
  20. De Mattia G; Bravi M.C.; Laurenti O; Cassone-Faldetta M; Armiento A; Ferri C; Balsano F, Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus, Metabolism 1998; 7(8):993-7.
  21. Demirkaya S, Topcuoglu MA, Aydin A, Ulas UH, Isimer AI, Vural O. Malondialdehyde, glutathione peroxidase and superoxide dismutase in peripheral blood erythrocytes of patients with acute cerebral ischemia. Eur J Neurol. 2001 Jan;8(1):43-51.
  22. Derekoy FS, Dundar Y, Aslan R, Cangal A. Influence of noise exposure on antioxidant system and TEOAEs in rabbits. Eur Arch Otorhinolaryngol. 2001 Dec;258(10):518-22.
  23. Dröge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc. 2000 Nov;59(4):595-600.
  24. Erden-Inal M, Sunal E, Kanbak G. Age-related changes in the glutathione redox system. Cell Biochem Funct. 2002 Mar;20(1):61-6.
  25. Fechter LD, Klis SF, Shirwany NA, Moore TG, Rao DB. Acrylonitrile produces transient cochlear function loss and potentiates permanent noise-induced hearing loss. Toxicol Sci. 2003 Sep;75(1):117-23.
  26. Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C. Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer. 2007 Dec 1;121(11):2381-6.
  27. Fidelus RK, Tsan MF. Glutathione and lymphocyte activation: a function of ageing and auto-immune disease. Immunology. 1987 Aug;61(4):503-8.
  28. Fläring UB, Rooyackers OE, Wernerman J, Hammarqvist F. Glutamine attenuates post-traumatic glutathione depletion in human muscle. Clin Sci (Lond). 2003 Mar;104(3):275-82.
  29. Fraternale A, Paoletti MF, Casabianca A, et al. Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem. 2006;13(15):1749-55.
  30. Gstraunthaler G, Pfaller W, Kotanko P. Glutathione depletion and in vitro lipid peroxidation in mercury or maleate induced acute renal failure. Biochem Pharmacol. 1983 Oct 1;32(19):2969-72.
  31. Geier DA, Geier MR A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm Res. 2006;66(4):182-8.
  32. Geier DA, Geier MR. A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorders. J Toxicol Environ Health A. 2007 May 15;70(10):837-51.
  33. Gentilhomme E, Neveux Y, Hua A, Thiriot C, Faure M, Thivolet J. Action of bis(betachloroethyl) sulphide (BCES) on human epidermis reconstituted in culture: Morphological alterations and biochemical depletion of glutathione. Toxicology in Vitro. 1992;6:139–147.
  34. Girardi G, Elías MM. Effect of different renal glutathione levels on renal mercury disposition and excretion in the rat. Toxicology. 1993 Jul 11;81(1):57-67.
  35. Giustarini D, Dalle-Donne I, Lorenzini S, Milzani A, Rossi R. Age-related influence on thiol, disulfide, and protein-mixed disulfide levels in human plasma. J Gerontol A Biol Sci Med Sci. 2006 Oct;61(10):1030-8.
  36. Gómez-Cambronero LG, Sabater L, Pereda J, et al. Role of cytokines and oxidative stress in the pathophysiology of acute pancreatitis: therapeutical implications. Curr Drug Targets Inflamm Allergy. 2002 Dec;1(4):393-403.
  37. Gras G, Porcheray F, Samah B, Leone C. The glutamate-glutamine cycle as an inducible, protective face of macrophage activation. J Leukoc Biol. 2006 Nov;80(5):1067-75.
  38. Grimble RF. Effect of antioxidative vitamins on immune function with clinical applications. Int J Vitam Nutr Res. 1997;67(5):312-20.
  39. Henderson D, Hu B, McFadden S, Zheng X. Evidence of a Common Pathway in Noise-Induced Hearing Loss and Carboplatin Ototoxicity. Noise Health. 1999a;2(5):53-70.
  40. Hong SY, Gil HW, Yang JO, et al. Pharmacokinetics of glutathione and its metabolites in normal subjects. J Korean Med Sci. 2005 Oct;20(5):721-6.
  41. Horton JW. Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology. 2003 Jul 15;189(1-2):75-88.
  42. Hsu M, Srinivas B, Kumar J, Subramanian R, Andersen J. Glutathione depletion resulting in selective mitochondrial complex I inhibition in dopaminergic cells is via an NO-mediated pathway not involving peroxynitrite: implications for Parkinson’s disease. J Neurochem. 2005 Mar;92(5):1091-103.
  43. James SJ, Slikker W 3rd, Melnyk S, New E, Pogribna M, Jernigan S. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology . 2005 Jan;26(1):1-8.
  44. James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):947-56.
  45. Ji LL. Oxidative stress during exercise: implication of antioxidant nutrients. Free Rad Biol Med 1995;18(6):1079-1086.
  46. Jones DP, Mody VC Jr, Carlson JL, Lynn MJ, Sternberg P Jr. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radic Biol Med. 2002 Nov 1;33(9):1290-300.
  47. Kharb S, Singh V, Ghalaut PS, Sharma A, Singh GP. Glutathione levels in health and sickness. Indian J Med Sci. 2000 Feb;54(2):52-4.
  48. Kientz CE. Chromatography and mass spectrometry of chemical warfare agents, toxins and related compounds: state of the art and future prospects, J Chromatogr A. 1998;814:1-23.
  49. Kim HJ, Barajas B, Chan RC, Nel AE. Glutathione depletion inhibits dendritic cell maturation and delayed-type hypersensitivity: implications for systemic disease and immunosenescence. J Allergy Clin Immunol. 2007 May;119(5):1225-33.
  50. Kopal C, Deveci M, Oztürk S, Sengezer M. Effects of topical glutathione treatment in rat ischemic wound model. Ann Plast Surg. 2007 Apr;58(4):449-55.
  51. Kopke RD, Coleman JK, Liu J, Campbell KC, Riffenburgh RH. Candidate’s thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope. 2002 Sep;112(9):1515-32.
  52. Kubic VL, Anders MW. Metabolism of carbon tetrachloride to phosgene. Life Sciences, 1980;26:2151-2156.
  53. Kulinskiĭ VI, Leonova ZA, Kolesnichenko LS, Malov IV, Danilov IuA. [Glutathione system in erythrocytes and plasma in viral hepatitis]. Biomed Khim. 2007 Jan-Feb;53(1):91-8.
  54. Laaksonen DE, Atalay M, Niskanen L, Uusitupa M, Hänninen O, Sen CK. Blood glutathione homeostasis as a determinant of resting and exercise-induced oxidative stress in young men. Redox Rep. 1999;4(1-2):53-9.
  55. Lailey AF, Hill L, Lawston IW, Stanton D, Upshall DG. Protection by cysteine esters against chemically induced pulmonary edema. Biochem Pharmacol. 1991;42:S47–S54.
  56. Lang CA, Mills BJ, Mastropaolo W, Liu MC. Blood glutathione decreases in chronic diseases. J Lab Clin Med. 2000 May;135(5):402-5.
  57. Lang CA, Mills BJ, Lang HL, et al. High blood glutathione levels accompany excellent physical and mental health in women ages 60 to 103 years. J Lab Clin Med. 2002 Dec;140(6):413-7.
  58. Lee WM. Acetaminophen and the U.S. acute liver failure study group: Lowering the risks of hepatic failure. Hepatology. 2004;40(1):6-9.
  59. Leeuwenburgh C, Ji LL. Glutathione depletion in rested and exercised mice: biochemical consequence and adaptation. Arch Biochem Biophys. 1995 Feb 1;316(2):941-9.
  60. Lichtenstein BS. Nutrition and HIV. STEP Perspect. 1995 Spring;7(1):2-5.
  61. Likidlilid A, Patchanans N, Poldee S, Peerapatdit T. Glutathione and glutathione peroxidase in type 1 diabetic patients. J Med Assoc Thai. 2007 Sep;90(9):1759-67.
  62. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2006 Aug;2(4):493-503.
  63. Lomaestro BM, Malone M. Glutathione in health and disease: pharmacotherapeutic issues. Ann Pharmacother. 1995 Dec;29(12):1263-73.
  64. Look MP, Rockstroh JK, Rao GS, et al. Serum selenium, plasma glutathione (GSH) and erythrocyte glutathione peroxidase (GSH-Px)-levels in asymptomatic versus symptomatic human immunodeficiency virus-1 (HIV-1)-infection. Eur J Clin Nutr. 1997 Apr;51(4):266-72.
  65. Macdonald J, Galley HF, Webster NR. Oxidative stress and gene expression in sepsis. Br J Anaesth. 2003 Feb;90(2):221-32.
  66. Martensson J, Meister A. Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4656-60.
  67. Martensson J, Han J, Griffith OW, Meister A. Glutathione ester delays the onset of scurvy in ascorbate-deficient guinea pigs. Proc Natl Acad Sci U S A. 1993 January 1; 90(1): 317–321.
  68. McFadden SL, Ohlemiller KK, Ding D, Shero M, Salvi RJ. The Influence of Superoxide Dismutase and Glutathione Peroxidase Deficiencies on Noise-Induced Hearing Loss in Mice. Noise Health. 2001;3(11):49-64.
  69. Meister A. Glutathione-ascorbate acid antioxidant system in animals. J Biol Chem. 1994;269:9397–400.
  70. Melhem A, Stern M, Shibolet O, et al.  Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. J Clin Gastroenterol. 2005 Sep;39(8):737-42.
  71. Melton L. The antioxidant myth: a medical fairy tale .New Scientist. August 2006. http://www.newscientist.com/article/mg19125631.500.html
  72. Moore A. The biochemistry of beauty: The science and pseudo-science of beautiful skin. EMBO Rep. 2002 August 15; 3(8): 714–717.
  73. Müller F, Svardal AM, Nordoy I, Berge RK, Aukrust P, Frøland SS. Virological and immunological effects of antioxidant treatment in patients with HIV infection. Eur J Clin Invest. 2000 Oct;30(10):905-14.
  74. Musiek ES, McLaughlin B, Morrow JD. Electrophilic cyclopentenone isoprostanes in neurodegeneration. J Mol Neurosci. 2007 Sep;33(1):80-6.
  75. Mutter J, Naumann J, Schneider R, Walach H, Haley B. Mercury and autism: accelerating evidence? Neuro Endocrinol Lett. 2005 Oct;26(5):439-46.
  76. Neri S, Ierna D, Antoci S, Campanile E, D’Amico RA, Noto R. Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. Panminerva Med. 2000 Sep;42(3):187-92.
  77. Noort D. Diagnosis of exposure to chemical warfare agents: A comprehensive literature survey 1990-2005. TNO Defense, Security and Safety. TNO-DV2 2005 A217
  78. Norman E, Dhairiwan R, Dargan PI, et al. PARACETAMOL POISONING: CAN IT BE PREVENTED? Proc R Coll Physicians Edinb 2001; 31:62-6.
  79. Ohinata Y, Yamasoba T, Schacht J, Miller JM. Glutathione limits noise-induced hearing loss. Hear Res. 2000 Aug;146(1-2):28-34.
  80. Osawa T, Kato Y. Protective role of antioxidative food factors in oxidative stress caused by hyperglycemia. Ann N Y Acad Sci. 2005 Jun;1043:440-51.
  81. Ozdemir G, Ozden M, Maral H, Kuskay S, Cetinalp P, Tarkun I. Malondialdehyde, glutathione, glutathione peroxidase and homocysteine levels in type 2 diabetic patients with and without microalbuminuria. Ann Clin Biochem. 2005 Mar;42(Pt 2):99-104.
  82. Pande M, Flora SJ. Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats. Toxicology. 2002 Aug 15;177(2-3):187-96.
  83. PR Leap. Awareness and Education Critical to Keeping the Population and the Antioxidant Market Thriving. July 23, 2007. http://www.prleap.com/pr/86502/
  84. Palamara AT, Perno CF, Ciriolo MR, et al. Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication. Antiviral Res. 1995 Jun; 27(3):237-53.
  85. Palamara AT, Garaci E, Rotilio G, et al. Inhibition of murine AIDS by reduced glutathione. AIDS Res Hum Retroviruses. 1996 Sep 20;12(14):1373-81.
  86. Qin XJ, He W, Hai CX, Liang X, Liu R.  Protection of multiple antioxidants Chinese herbal medicine on the oxidative stress induced by adriamycin chemotherapy. J Appl Toxicol. 2007 Jun 20 [Epub ahead of print]
  87. Rahman I. Regulation of glutathione in inflammation and chronic lung diseases. Mutat Res. 2005 Nov 11;579(1-2):58-80.
  88. Rahman I. Antioxidant therapies in COPD. Int J Chron Obstruct Pulmon Dis. 2006;1(1):15-29.
  89. Reynolds A, Laurie C, Mosley RL, Gendelman HE. Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol. 2007;82:297-325.
  90. Robinson MK, Rodrick ML, Jacobs DO, et al. Glutathione depletion in rats impairs T-cell and macrophage immune function. Arch Surg. 1993 Jan;128(1):29-34; discussion 34-5.
  91. Samiec PS, Drews-Botsch C, Flagg EW, et al. Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med. 1998 Mar 15;24(5):699-704.
  92. Schmidinger M, Budinsky AC, Wenzel C, et al. Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer. Wien Klin Wochenschr. 2000 Jul 28;112(14):617-23.
  93. Sciuto AM, Hurt HH. Clinical Drug Treatment of Edemagenic Gas-Induced Lung Injury (1998). {http://handle.dtic.mil/100.2/ADA417836},{Defense Technical Information Center OAI-PMH Repository [http://stinet.dtic.mil/oai/oai] (United States)}
  94. Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, Rosati G. Reduced intravenous glutathione in the treatment of early Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct;20(7):1159-70.
  95. Sen CK, Atalay M, Hänninen O. Exercise-induced oxidative stress: glutathione supplementation and deficiency. J Appl Physiol. 1994 Nov;77(5):2177-87.
  96. Sen CK. Oxidants and antioxidants in exercise. J Appl Physiol. 1995 Sep;79(3):675-86.
  97. Sen CK, Packer L. Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr. 2000 Aug;72(2 Suppl):653S-69S.
  98. Sen CK (2001a). Antioxidants in exercise nutrition. Sports Med. 2001;31(13):891-908.
  99. Sen CK (2001b). Update on thiol status and supplements in physical exercise. Can J Appl Physiol. 2001;26 Suppl:S4-12.
  100. Sian J, Dexter DT, Lees AJ, Daniel S, et al. Alterations In Glutathione Levels In Parkinson’s Disease And Other Neurodegenerative Disorders Affecting Basal Ganglia. Ann Neurol. 1994;36(3);348-55.
  101. Sidell FR, Urbanetti JS, Smith WJ. Chapter 7: Vesicants. In: Medical Aspects of Chemical and Biological Warfare. Department of the Army, Office of The Surgeon General, Borden Institute. 1997 pgs: 197-228.
  102. Simone CB 2nd, Simone NL, Simone V, Simone CB. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2. Altern Ther Health Med. 2007 Mar-Apr;13(2):40-7.
  103. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol. 1997 Jun;8(6):569-73.
  104. Spooner JB, Harvey JG. Paracetamol overdosage – facts not misconceptions. Pharmaceutical Journal 1993; 250:706-7.
  105. Surapaneni KM, Venkataramana G. Status of lipid peroxidation, glutathione, ascorbic acid, vitamin E and antioxidant enzymes in patients with osteoarthritis. Indian J Med Sci. 2007 Jan;61(1):9-14.
  106. Valko M, Morris H, Cronin MT. Metals, Toxicity And Oxidative Stress. Curr Med Chem. 2005;12(10):1161-208.
  107. Urano T, Naganuma A, Imura N. Species differences in biliary excretion of methylmercury–role of non-protein sulfhydryls in bile. Res Commun Chem Pathol Pharmacol. 1988 Nov;62(2):339-51.
  108. Urbanetti JS. Chapter 9 TOXIC INHALATIONAL INJURY. In: Medical Aspects of Chemical and Biological Warfare. Department of the Army, Office of The Surgeon General, Borden Institute. 1997 Pages: 247-270.
  109. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial”. JAMA 2006;296 (1): 87–93.
  110. Wright T. Antioxidant Update. Nutraceuticals World. March 2004 http://www.nutraceuticalsworld.com/articles/2004/03/antioxidants- update.php
  111. Wright R. Antioxidant Avalanche. Nutraceuticals World. March 2005. http://www.npicenter.com/anm/templates/newsNWTemp.aspx? articleid=11986&zoneid=49
  112. Yamasoba T, Nuttall AL, Harris C, Raphael Y, Miller JM. Role of glutathione in protection against noise-induced hearing loss. Brain Res. 1998 Feb 16;784(1-2):82-90.
  113. Yang CS, Chou ST, Liu L, Tsai PJ, Kuo JS. Effect of ageing on human plasma glutathione concentrations as determined by high-performance liquid chromatography with fluorimetric detection. J Chromatogr B Biomed Appl. 1995 Dec 1;674(1):23-30.
  114. Zhang K, Yang EB, Wong KP, Mack P. GSH, GSH-related enzymes and GS-X pump in relation to sensitivity of human tumor cell lines to chlorambucil and adriamycin. Int J Oncol. 1999 May;14(5):861-7.
  115. Zimmermann C, Winnefeld K, Streck S, Roskos M, Haberl RL. Antioxidant status in acute stroke patients and patients at stroke risk. Eur Neurol. 2004;51(3):157-61.