Increasing intracellular glutathione levels has been identified as a potential strategy for treating many diseases and disorders. The obvious approaches of increasing dietary intake of glutathione and/or cysteine are generally ineffective in increasing cellular glutathione content. Transport of glutathione either across the cell membrane, or from the intestinal contents is thermodynamically unfavourable. This is due to the extreme concentration gradient between the intracellular glutathione content (1-10 mM) and the extracellular concentration (plasma 2-10 nM). Orally or intravenously administered glutathione is not effectively transported into cells and is degraded into its component amino acids extracellularly. In contrast to glutathione, there is no thermodynamic limitation to the transport of extracellular GGC across cell membranes and GGC is readily taken up by many cell types where it is converted directly into glutathione. Administration of cysteine is ineffective as it rapidly oxidizes to poorly soluble cystine and is also reportedly toxic.
The development of strategies to increase glutathione levels has been comprehensively reviewed by (White 1994), (Sen 1997), (Kidd 1997), (Anderson 1998a), (Anderson 1998b), (Sen 1998), (Griffith 1999), (Wernerman 1999), (Lu 2000), (Deneke 2000), (Reid 2001), (Valencia 2001) and (Valencia 2002). The review articles were specifically written for medical researchers and clinicians interested in evaluating the therapeutic effect of raising glutathione levels initially in animal models of disease and later in human trials. Several of the reviews report various beneficial effects of glutathione repletion in animal experiments and preliminary human clinical studies.
The initial successes reported by the above reviewers have led to a flood of articles over the past five years reporting the therapeutic use of glutathione precursors in the treatment of human diseases. The key findings of clinical trials with specific diseases have been reported in the review articles listed in Table 3.1. The data presented by the reviewers strongly confirm the detrimental role of oxidative stress in human disease development. They specifically identify glutathione repletion as a potentially effective treatment strategy.
By far the most commonly used glutathione repletion agent is N-acetylcysteine and this is most probably due to the fact that N-acetylcysteine has been used with relative safety in humans since 1965 as a mucolytic (mucus reducing agent), and since 1984 as an antidote to paracetamol overdose (Linden 1984). Pure GGC has not been used in any clinical trial as yet and this is presumably due to its high cost and lack of availability. However, GGC occurs naturally in bovine milk and is especially rich in the whey fraction where it occurs linked via a disulphide bond to milk proteins. Numerous reports have demonstrated that the consumption of whey proteins increases levels of glutathione (Bounous 2000). Many commercially available whey protein isolates claim GGC to be the key bioactive constituent. Recent human clinical trials investigating muscle performance (Lands 1999), HIV patients (Micke 2002) and strenuous exercise (Middleton 2004) have confirmed that whey protein isolates effectively increase glutathione levels, albeit by only a small amount. High grade GGC as develped by Biospecialties will specifically targed and greatly increase intracellular glutathione production.