Aging: The aging process is associated with deterioration of GSH homeostasis. Plasma GSH trends lower while GSSG becomes more elevated7 Limited data suggests higher GSH levels correlate with better health, regardless of age, and that subjects with chronic disease have poorer GSH status than those free of disease. 12 Exercise training can strengthen GSH homeostasis.37 With progressively more disease states manifesting GSH deficiency, repletion is a viable preventive, therapeutic, and anti-aging strategy.
Glutathione Repletion Strategies
Oral/I.V. Glutathione: Tradition holds that GSH is not systemically bioavailable when given by mouth.40 However, copious data confirm it is efficiently absorbed across the intestinal epithelium, by a specific uptake system.41,42 Catabolism of newly-absorbed GSH after it reaches the portal blood intact but prior to its accessing the liver accounts for the paradoxical findings.43 Such breakdown of circulating GSH does not rule out its oral use for GI conditions such as Crohn’s Disease.28
Results from two controlled trials seem to suggest oral GSH had no significant benefit, but do not rule out benefit from high-dose GSH to depleted subjects.4,40 In one trial, the plasma concentration was high-normal at baseline. In the second, the dose administered (to cirrhosis patients), at 300 mg/day for 28 days, may have been insufficient to replete liver GSH in the context of severe impairment of biosynthesis.4
Perlmutter reported case histories indicating success with GSH repletion in various neurodegenerative diseases.44 He reported marked benefit from its intravenous administration in Parkinson’s, and successful oral application of orthomolecular GSH precursors to cases of Alzheimer’s, stroke, multiple sclerosis, amyotrophic lateral sclerosis, and post-polio syndrome.
N-acetylcysteine: Cysteine availability most often limits GSH biosynthesis in vivo. One orally bioavailable cysteine source is N-acetylcysteine (NAC). NAC is a potent antioxidant with antimutagenic and anticarcinogenic properties, and an established antidote for acetaminophen overdose known to deplete liver GSH. Oral dosing with NAC supplants oral L-cysteine, which is highly unstable and potentially toxic.45
Following its intestinal absorption, NAC is converted to circulating cysteine and can effectively replenish GSH in depleted patients.46 In HIV/AIDS, plasma GSH and cysteine levels are often low. Two clinical trials, one of them double-blind, reported NAC had clinical benefit.3 Administered intravenously or as an infusion over 15-30 minutes, it can replete glutathione in the ELF and improve lung function in patients with septic shock.10 In one trial on pulmonary disease, oral NAC at 1800 mg/day failed to increase GSH.47
Alpha-Lipoic Acid (ALA): The antioxidant alpha-lipoic acid (ALA) is another effective GSH repleter. Orally, it raises GSH levels in HIV patients,48 and is extremely safe and well tolerated.49 ALA is a broad-spectrum, fat- and water-phase antioxidant with potent electron-donating capacity, and has added biochemical versatility as a Krebs cycle cofactor and transition metal chelator. It is superior to NAC in being recyclable in vivo from its oxidized form.
Methionine, Ascorbic Acid, Taurine: Oral L-methionine is a cysteine precursor but can cause nausea and vomiting, whereas its activated counterpart S-adenosylmethione (SAMe) is well tolerated. When given i.v. in high doses to cirrhotic patients, SAMe repleted erythrocyte GSH.13 Ascorbate conserves intracellular glutathione and probably is a redox GSH cofactor.16 Taurine is a sulfur amino acid which, given orally, can raise the platelet aggregation threshold and increase platelet GSH in healthy males.2
Other Methods of Glutathione: Repletion One synthetic cysteine delivery agent is L-2-oxothiazolidine-4-carboxylate (OTC, Procysteine), which can be enzymatically converted to cysteine within liver cells. Oral OTC is converted to GSH in humans.12 Given intravenously to HIV patients, it increased blood GSH levels after six weeks of treatment.50 In patients with coronary artery disease, oral OTC markedly improved arterial flow-mediated dilation.51
Glutathione esters have been heavily researched as potential oral delivery compounds but their long-term safety is in question. Their reported toxicity is perhaps attributable to metal impurities.3
GSH and other thiols tend to be sensitive to redox-active minerals, and care should be taken to omit these from therapeutic preparations. GSH use in cancer must be approached with caution, since some tumors may utilize it intracellularly to resist chemotherapy drugs.19
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