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Glutathione catalyzes glutathione S-transferases (GST) and glutathione peroxidases (GPx). Thus, playing a role in detoxification by eliminating toxic electrophilic molecules and reactive peroxides. Glutathione plays a crucial role in a detoxification system that is fundamental in plants, mammals, and fungi.3
Aside from its detoxification role it is important for a variety of essential cellular reactions. Its presence in the glyoxalase system, is fundamental to DNA and RNA nucleotide reduction. Glutathione is also a constituent in the regulation of protein and gene expression, exchange reactions including thiol to disulfide ratios involve glutathione.4
Glutathione can exist intracellularly in either an oxidized (glutathione disulfide) or reduced (glutathione) molecular state. The ratio of reduced glutathione to glutathione disulfide has been shown to be critical in cell survival, this system is very tightly regulated.
Deficiency of glutathione puts the cell at risk for oxidative damage. An imbalance of glutathione is present in many pathologies including cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging.
Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 degrees C in a 1.0 M aqueous medium at pH 2.0-5.0 (1) and 4.5-6.8 (2-4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH]tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH]tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1-4 by GS- are (1.43 +/- 0.01) x 10(7), (3.86 +/- 0.03) x 10(6), (1.83 +/- 0.01) x 10(6), and (1.18 +/- 0.01) x 10(6) M(-1)s(-1), respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-C1 axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds.
Clinical trial data regarding the effectiveness of glutathione treatment is conflicting or lacking for most medical conditions. Always talk to your doctor first before you use any non-prescription dietary supplement.
Glutathione is an antioxidant made in all human cell and helps to prevent cell damage due to oxidizing free radicals. It is made in the liver using the amino acids L-glutamate, cysteine and glycine. High levels of glutathione exists in the cell, at the same concentrations as glucose (blood sugar), potassium and cholesterol. It is also naturally present in many foods (see below).
In addition to inhibiting oxidation due to free radicals, it also helps with tissue repair and protein manufacturing needed by the body. However, when glutathione itself is exposed to oxidative stress, such as with toxic chemicals, levels of glutathione in the body can decline. Disease, poor diet, aging and excess stress can also deplete your glutathione levels and may contribute to poor health.
N-acetylcysteine (NAC), a precursor to glutathione, has been used to raise its levels. NAC is often used as antidote in acetaminophen (Tylenol) overdose. Call 911 for emergency medical help for any overdose situation.
Glutathione supplements are often used by patients with chronic health conditions such as HIV, type 2 diabetes mellitus, and cancer, but evidence to prove any benefit is lacking. The reliable absorption of oral formulations is controversial and studies have been split on its effectiveness. Formulations of liposomal glutathione may be more effective, but further research is needed.
A glutathione supplement may be beneficial in patients low in this antioxidant, such as patients with cystic fibrosis, AIDS, Alzheimer's or Parkinson's disease, but you should make this decision only in conjunction with your doctor.
Yes, glutathione can be found naturally in many cruciferous vegetables, such as broccoli, cauliflower, cabbage, and brussels sprouts. Avocados, potatoes, carrots, asparagus, spinach, squash and okra also contain this antioxidant. Onions, garlic and fruits like watermelon also carry glutathione.
Antioxidants, in general, can also be found in vitamins C, E, and carotenoids (beta-carotene) found in orange, red and yellow vegetables like carrots, pumpkins, peppers, squash, tomatoes and in salmon. Supplemental cysteine in the form of whey, alcohol-free beer and almonds have also been reported to increase glutathione levels. Even meditation (which may lower stress) has been suggested to raise glutathione.
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
The obvious strategy is to directly administer glutathione. This can be done orally, topically, intravenously, intranasally, or in nebulized form. Glutathione administered intravenously, inhaled, and ingested intranasally increases systemic levels.27 IV glutathione has a short half-life but has shown at least short-term efficacy in several diseases. Oral administration is controversial; while most research shows that oral glutathione does not increase RBC glutathione, there are a few studies that show efficacy.28 My opinion is that unmodified oral glutathione is unlikely to consistently elevate cellular levels. Oral and transdermal liposomal glutathione show promise, but research is early.29
Finally, we can provide specific nutrients to promote glutathione production. As noted above, cysteine availability is the rate-limiting step in the de novo production of glutathione. While oral cysteine does not make it through the digestive track, supplemental cysteine in the form of whey or N-acetylcysteine (NAC) is effective at raising levels. While there is substantial variation, 1000 mg/d of NAC will substantially increase glutathione in virtually all patients.30 For the rare patient who reacts to NAC, SAMe can be used.31 Do not use methionine as it will increase homocysteine. Interestingly, supplementing with NAC (600 mg/d for 4 wk) decreases GGT 25%, suggesting that increasing de novo synthesis decreases the need for GGT recycling.32
For those looking for a nonsupplemental solution, 500 mL of alcohol-free beer per day raises RBC glutathione 29%!33 There are many other examples of foods that increase glutathione. For example, 83 g/d of almonds increases glutathione in smokers by 16% and decreases their DNA damage by 29%.34
IV glutathione is marketed for skin lightening because oral supplements have low bioavailability, but there is also little to no research to support this therapy. Additionally, research done in the Philippines found several severe adverse effects of IV glutathione, including:
Sechi G, Deledda MG, Bua G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7):1159-1170. doi:10.1016/s0278-5846(96)00103-0
Marrades RM, Roca J, Barberà JA, de Jover L, MacNee W, Rodriguez-Roisin R. Nebulized glutathione induces bronchoconstriction in patients with mild asthma. Am J Respir Crit Care Med. 1997;156(2 Pt 1):425-430. doi: 10.1164/ajrccm.156.2.9611001
Sitohang IBS, Anwar AI, Jusuf NK, Arimuko A, Norawati L, Veronica S. Evaluating oral glutathione plus ascorbic acid, alpha-lipoic acid, and zinc aspartate as a skin-lightening agent: an Indonesian multicenter, randomized, controlled trial. J Clin Aesthet Dermatol. 2021;14(7):E53-E58.
FDA received an adverse event report on January 14, 2019, regarding seven patients in an outpatient clinic who received intravenous injections containing L-glutathione 200mg/mL compounded by a pharmacy using L-glutathione repackaged by Letco (lot number: 1810150050, expiration date: 6/17/2020). According to the report, each patient was administered 7mL (1,400mg) of L-glutathione by injection on January 9, 2019. Within minutes of the infusion, the patients reportedly experienced symptoms of varying degrees, including nausea, vomiting, lightheadedness, chills, body aches and sneezing. One of the patients experienced low blood pressure and difficulty breathing and was subsequently transferred to a hospital.
FDA received another adverse event report on February 4, 2019, associated with an intravenous injection of a drug containing L-glutathione 200mg/mL compounded by a different pharmacy that also used L-glutathione repackaged by Letco (lot number: 1808030045, expiration date: 6/17/2020). According to the report, the patient received an infusion of 12mL (2,400mg) of L-glutathione on October 17, 2018, and experienced sudden chills, fever and shaking, and was subsequently admitted to the hospital for a possible bloodstream infection. 59ce067264
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