Glutathione 1500 mg

Glutathione is a tripeptide assembled from L-glutamate, L-cysteine and glycine, molecular formula C10H17N3O6S, molecular weight 307.32 g/mol, CAS 70-18-8. Its defining structural feature is the bond at the glutamate end. Rather than the usual alpha-carboxyl linkage found in ribosomal peptides, the amide forms between the side-chain gamma-carboxyl of glutamate and the amino group of cysteine. ChEBI records the molecule as glutamic acid attached via its side chain to the N-terminus of cysteinylglycine, and the PubChem IUPAC name places the amide at the fifth carbon of the glutamate backbone. That single difference is why the molecule is written gamma-Glu-Cys-Gly and why the one-letter abbreviation ECG is misleading. The gamma bond is not a substrate for common aminopeptidases; cleavage is instead carried out by gamma-glutamyl transpeptidase, an ectoenzyme on the outer surface of the cell membrane.

The reactive centre is the free thiol on the cysteine residue. Two molecules of the reduced form (GSH) couple through that thiol to form a disulfide-linked dimer, oxidised glutathione (GSSG), a separate compound with the formula C20H32N6O12S2 and a molecular weight of 612.6. The ratio between the two species is the property most often measured in the laboratory, because it changes faster than total glutathione content. This redox chemistry also governs handling: the reduced powder is stable dry, but in aqueous solution and in contact with air it converts to GSSG.

Glutathione is not a translated peptide. Lu (2013) describes its production as a two-step, ATP-dependent enzymatic route: glutamate cysteine ligase (GCL) joins glutamate and cysteine to make the gamma-glutamylcysteine intermediate, then glutathione synthetase (GS) adds glycine. Because no ribosome is involved, it is manufactured commercially by microbial fermentation (typically yeast) or by enzymatic and chemical synthesis, then purified. Material supplied here is the reduced form at >=99% purity, 1500 mg per vial, for laboratory research use only and not for human consumption.

The background biochemistry of glutathione is one of the better-characterised areas of cell biology, and the literature on it is very large. The literature on administering glutathione as a compound is a much smaller and considerably less settled body of work. These two things are frequently conflated. What follows separates them.

On absorption from the gut, the published results conflict. Witschi and colleagues (1992) gave seven healthy volunteers a single oral dose of 0.15 mmol/kg, roughly 3 g, and measured plasma glutathione, cysteine and glutamate over 270 minutes. From a baseline plasma glutathione concentration of 6.2 micromol/L, none of the three rose significantly, and the authors attributed this to hydrolysis by intestinal and hepatic enzymes. Two decades later Richie and colleagues (2015) ran a 6-month randomised, double-blind, placebo-controlled trial in 54 healthy non-smoking adults. In the 1,000 mg/day arm they reported increases of 30 to 35 percent in erythrocyte, plasma and lymphocyte glutathione and 260 percent in buccal cells at 6 months (P less than 0.05); the 250 mg/day arm showed 17 percent in blood and 29 percent in erythrocytes (P less than 0.05). The authors also reported that levels returned to baseline after a one-month washout period, and that natural killer cytotoxicity increased more than twofold in the high-dose group versus placebo (P less than 0.05) at 3 months.

Allen and Bradley (2011) measured downstream oxidative-stress markers rather than glutathione content and reported a null result. They randomised 40 volunteers to 500 mg twice daily or placebo for four weeks and measured urinary F2-isoprostanes and 8-hydroxy-2'-deoxyguanosine. Neither differed between groups (F2-isoprostane change 0.0 plus or minus 0.1 versus 0.0 plus or minus 0.1, p = 0.38; 8-OHdG change -0.2 plus or minus 3.3 versus 1.0 plus or minus 3.2, p = 0.27), and the authors reported that total reduced, oxidised and ratio measures of glutathione status were also unchanged.

The dermatological literature examines skin melanin indices. Arjinpathana and Asawanonda (2012) randomised 60 healthy medical students to 500 mg/day orally in two divided doses or placebo for four weeks, measuring melanin index at six body sites. Melanin indices fell at all six sites in the glutathione arm; the difference against placebo reached statistical significance at two of them, the right side of the face (p = 0.021) and the sun-exposed left forearm (p = 0.036). The authors' own stated conclusion was that the effect was seen in a small number of subjects and that long-term safety has not been established and warrants more extensive clinical trials.

Studies using the parenteral route have the thinnest evidence base of all. Zubair and colleagues (2016) ran a placebo-controlled study in Pakistan: 50 women enrolled, 32 completed, with 16 receiving 1,200 mg intravenous glutathione with vitamin C twice weekly for six weeks (12 injections) against intravenous placebo. Six of 16 (37.5 percent) improved versus 3 of 16 (18.7 percent) on placebo, which did not reach significance (p = 0.054), and by six months after the last injection only one subject retained the change. The authors recorded adverse effects in all subjects, with deranged liver function tests in 8 and one case of anaphylaxis, both severe enough to warrant discontinuation. Davids, Van Wyk and Khumalo (2016), reviewing the field in the South African Medical Journal, reported finding no studies of intravenous glutathione for skin lightening or of its safety for chronic use, and called for regulatory review. Taken together, the controlled human record for administered glutathione is small, internally inconsistent on oral bioavailability, and for the intravenous route amounts to a single small study that did not meet its significance threshold.