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Glutathione: Potential uses and methods of administration:

Glutathione supplementation offers potential benefit in many conditions, yet lingering questions about actual absorption have me hesitant how to use it. Let me start by summarizing some of the uses for glutathione and then discuss the confusing points.

Glutathione is synthesized from the amino acid cysteine, glutamate and glycine. It acts, when in its reduced form, as one of the major detoxifiers in the body. Riboflavin, niacinamide, selenium, and glutathione reductase are all essential cofactors for generating reduced glutathione. Cysteine is poorly absorbed so it is often given as N-acetyl-cysteine. Glutathione is found in almost all cells. The liver, spleen, pancreas, and lens and cornea of the eye have the highest concentrations. Glutathione levels decrease with age. It acts as an antioxidant, protecting proteins, aiding liver detoxification and helping remove heavy metals from the body and is considered an essential antioxidant factor in slowing aging.

Parkinson's Disease is one of the several diseases where glutathione may play an important role. Many of the things which have been suggested as possible causes of Parkinson's Disease (including pesticides, iron, copper, zinc, manganese, mercury, lead, aluminum, and certain food borne toxins) are all oxidative stressors which deplete glutathione levels in the substantia nigra of the brain. A theory has been proposed [1] that low levels of glutathione put people at greater risk for developing Parkinson's. Experiments in administering glutathione to newly diagnosed patients produce striking improvement in function.[ 2 ,3] When given 600 mg twice a day for 30 days patients showed an average of 42% decline in disability.[4]

Glutathione plays several roles in cancer. It prevents cancer, protecting DNA from damage by detoxifying harmful chemicals and removing them from the body. Low glutathione levels predispose people to cancer. “Patients with a variety of malignant disorders were found to have a markedly lowered plasma glutathione level.”[5].

Glutathione also fights cancer. It selectively stimulates apoptosis (cell death) of malignant cells while leaving healthy cells unaffected.[6] It does this by regulating the tumor suppressor protein p53. Under normal conditions the p53 protein senses DNA damage in a cell and slows the rate of cell division, giving the cell time to repair itself. If the DNA cannot be repaired, p53 tells the cell to kill itself (apoptosis). Treatment with glutathione may reverse the cancer process. Various studies have shown glutathione reverses development of neuroblastoma, cervical carcinoma, leukemia, and other cancers.[7]

It also seems useful to combine glutathione with certain chemotherapy drugs, especially cisplatin, cyclophosphamine, and bleomycin. Glutathione decreases the toxic side effects of these drugs while either not affecting or increasing their therapeutic effect. Glutathione protects against nerve damage when using cisplatin to treat gastric [8] or ovarian cancer [9].

Its use with ovarian cancer is especially interesting. Ovarian cancer frequently responds to chemotherapy treatment in a dose dependent manner but toxic side effects frequently limit the amounts given. Using glutathione in conjunction with chemotherapy allows the use of higher more effective drug levels. [10]

A similar benefit is seen with radiation therapy. Administering glutathione prior to radiation treatment reduces unwanted side effects.[11, 12]

There isn't debate about whether there is a benefit to having high levels of reduced glutathione in the body. The question is how to get it there.

Direct supplementation with glutathione is complicated. Proponents have strong feelings on how it should be done. Some say it can be absorbed orally and advocate oral dosing.[13, 14] Others say oral dosing doesn't work and it must be given IV. The chemotherapy studies showing decreased side effects administered glutathione through an intravenous saline solution just prior to chemotherapy. The work with Parkinson's also used IV dosing. One study which argues against oral administration, gave test subjects a single large 3 gram dose of glutathione and saw no increase in plasma levels.[15] Enzymes in the digestive process apparently destroy the glutathione. On the other hand, there are studies which used oral glutathione with benefit. In one a 5 gram/day dose of glutathione slowed the progression of liver cancer.[16]

Can we explain the differences in results? Those who say oral dosing is effective are specific on how to take it: on an empty stomach followed by a full glass of water. This may explain the varying results: some studies may have administered it on an empty stomach and others with food. The study which gave 3 gram single doses were using hepatitis patients as test subjects. Perhaps they were so depleted in glutathione they quickly used up the first dose and would have needed repeated doses to raise their levels.

One group has attempted to overcome the challenge of administering oral glutathione and increased its effectiveness by combining it with anthocyanins. These bioflavinoids form the dark red and purple color found in certain plants such as blueberries, elderberry and beets. Apparently anthocyanins possess the ability to regenerate glutathione from oxidized glutathione even in the presence of oxidizing agents, free radicals, and toxic exposure.[17] This combination is sold as Recancostat by Tyler Encapsulations.

Another method of glutathione administration is to inhale it. Glutathione prepared in sterile saline solution is turned into a cool mist using a nebulizer of the sort used to treat asthma, and inhaled. Good results have been reported using this method to treat emphysema.[18] This method of administration has been suggested for treating lung tumors.[19] It is unclear whether this raises plasma levels or just has a localized effect on the lung tissue.

Although there are conflicting opinions, a few things are clear. It is good to have high levels of reduced glutathione in the body. They slow aging and prevent all sorts of disease. In a person who has either Parkinson's, cancer, or other conditions linked with oxidative stress, it's sensible to increase glutathione levels. Increasing levels of Vitamin C, vitamin E, selenium, cysteine, glutamine and glycine may be enough to do this. In urgent situations, when one desires the highest possible levels, supplementing with reduced glutathione itself may be the right choice. If undergoing chemotherapy with the platinum drugs, or if one has Parkinson's, IV administration appears to be the preferred, or at least best documented, method. If taking glutathione orally, it should be taken on an empty stomach followed with water. If you believe the anthocyanin theory, use Recancostat. If unwilling to pay the premium price that Recancostat sells for, theoretically a similar effect might be achieved by taking a supplement high in anthocyanins at the same time: for example bilberry, or elderberry extract or even beet juice.

References:
1. Bains JS, Shaw, CA. Neurodegenerative disoreders in humans: the role of glutathione in oxidative stess- mediated neuronal death. Brain Res Rev 1997;25:335-358
2. Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Progr Neuropsychopharmacol Biol Psychiatry 1996;20:1159-70.
3. Perlmutter D. BrainRecovery.com: Po werful Therapy for challenging Brain Disorders. Naples FL: The Perlmutter Health Center (brainrecovery.com) 2000
4. Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Progr Neuropsychopharmacol Biol Psychiatry 1996;20:1159-70.
5. Beutler E., and Gelbart T. Plasma glutathione in health and in patients with malignant disease. J Lab Clin Med , 1985: 105;581-584.
6. Donnerstag B, et al. Reduced glutahione and S-acetylgluathione as slective apoptosis inducing agents in cancer therapy. Cancer Letters 1996;110 :63-70.
7. Rotstein JB, Slaga TJ, Effects of exogenous glutathione on tumor progression in the murine skin of multistate carcinogenesis model. Carcinogenesis. ((9): 1547-51, 1988
8. Cascinu Stefano et al. Neuroprotective effect of reduced glutathione on sicplatin-based chemotherapy in advanced gastric cancer: a randomised double blind placebo-controlled trial. J. clinical Oncology 13:26-32, 1995
9. Tedeschi M, et al. The role of glutathione in combination with cisplatin in the treatment of ovarian cancer. Cancer Treatment Reviews 18:253-259, 1994
10. Francesco Di Re et al. Efficacy and safety of high dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer. Cancer Chemother Pharmacol 25:335-360 1990
11. De Maria Faichi, and Venturino. Adjuvant radiotherapy of the pelvis with or without reduced glutathione: a randomised trial in patients operated on for endometrial cancer.Tumori 78:374-376 1992.
12. Bhattathiri VN et al. Influence of plasma GSH levels on acute radiation mucositis of the oral cavity. Int J Radiat Oncol Biol Phys 1994 May 15;29(2):383-6
13. Hagen T, et al. Bioavailability of dietary glutathione: effect on plasma concentration. Am J of Physiol. 259:G524 - G 529, 1990
14. Favilli, F. et al. Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters. British Journal of Nutrition 1997;78: 293-300
15. Witschi A et al. The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992;43:667-669
16. Dahlhoof, K. et al. Glutathione treatment of hepatocellular carcinoma. Liver 1992:12; 341-343
17. Ohlenshager G, Treusch G. Reduced glutathione and anthocyanins: redox cycling and redox recycling in living systems. Praxis-Telegramm 1994;(61)1-20
18. Lamson, DW and Brignal l MS. the use of nebulized glutathione in the treatment of emphysema: a case report. Alt Med Rev 2000;5(5):429-431.
19. conversation, Tim Birdsall, ND, Cancer Treatment Centers of America


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