A number of strategies have evolved to raise levels in depleted individuals. As shown in Fig. 7.7, there are three potential ways of enhancing cellular GSH content: administration of the three amino acids (cysteine, glutamic acid and glycine) that comprise the tripeptide, either singly or in various combinations; administration of cofactors for the metabolic pathways leading to GSH production, i.e. vitamin B6, riboflavin and folic acid; and administration of synthetic compounds that become converted to precursors of GSH.
While cysteine supplies are the primary determinant of the ability to synthesize GSH, in some circumstances an insufficiency in the other two amino acids from which it is made might limit synthesis. Glutamine (a precursor of glutamate), for example, has been shown to maintain hepatic GSH in animals poisoned with acetaminophen, to enhance gut GSH synthesis in rats when given by gavage and to enhance hepatic GSH synthesis when given intravenously to rats (Cao et al., 1998). In human studies a similar effect on gut GSH concentrations was noted (O'Riordain et al., 1996). Glycine supplements have been shown to raise hepatic GSH in rats exposed to haemorrhagic shock (Spittler et al., 1999). In this condition, however, the metabolic demand for glycine is increased, since glycine is the sole nitrogen donor for haem synthesis and would therefore become rate-limiting for GSH synthesis. There are many studies that illustrate the ability of sulphur amino acid availability to influence tissue GSH concentrations (e.g. Stipanuk et al., 1992).
Studies using animal models of inflammation have shown that a low-protein diet will suppress glutathione synthesis, a situation that is reversed by the provision of cysteine or methionine (Hunter and Grimble, 1994, 1997). Beneficial effects on immune function, morbidity and mortality were observed in burned children when additional protein in the form of whey protein (the milk protein richest in sulphur amino acids) was fed (Alexander et al., 1980).
Because cysteine is unstable in its reduced form, toxic in high doses and mostly degraded in the extracellular compartment, several compounds have been used to deliver cysteine directly to cells. These include L-2-oxothiazalidine-4-carboxylate (OTZ) and NAC. OTZ is an analogue of 5-oxoproline, in which the 4-methylene moiety has been replaced with sulphur. It provides an excellent substrate for 5-oxoprolinase (an intracellular enzyme). The enzyme converts OTZ to S-carboxy-L-cysteine, which is rapidly hydrolysed to L-cysteine. NAC rapidly enters the cell and is speedily deacylated to yield L-cysteine. Recent animal and clinical trials with NAC and OTZ have demonstrated the ability of the compounds to enhance GSH status (Bernard et al., 1997; Deneke, 2000; De Rosa et al., 2000). In studies on patients with sepsis, NAC infusion was shown to increase blood GSH, decrease plasma concentrations of IL-8 and soluble TNF receptors (an index of TNF production), improve respiratory function and reduce the number of days needed in intensive care (Bernard et al., 1997; Spapen et al., 1998). While not affecting mortality rates, NAC shortened hospital length of stay by > 60%. OTZ increased whole-blood GSH in peritoneal-dialysis patients, normalized tissue GSH in rats fed a sulphur amino acid-deficient diet and decreased the extent of inflammation in a rat peritonitis model (Bernard et al., 1997). In a randomized, double-blind, controlled study on asymptomatic HIV-infected patients, oral OTZ treatment increased GSH concentrations in whole blood (Breitzkreutz et al., 2000). Other randomized studies on asymptomatic HIV+ patients in the presence and absence of anti-retroviral therapy (ART) have shown that NAC can raise blood
GSH, increase natural killer cell activity and enhance stimulation indices of T-cells incubated with mitogen or tetanus toxin (Simon et al., 1994; Breitzkreutz et al., 2000). Interestingly, the rise in T-cell function was accompanied by a fall in plasma IL-6 in subjects receiving ART as well as the drug. Furthermore, studies have shown that survival time was improved in HIV+ patients who maintained high concentrations of GSH in CD4+ T lymphocytes (Herzenberg et al., 1997). It could therefore be surmised that improved T-cell function and reduced inflammation are modulated by improvement in antioxidant status in these patients. Alpha-lipoic acid provides a further means of enhancing tissue GSH content (Deneke, 2000). The compound is reduced to dihydrolipoic acid, which converts cystine to cysteine. This change has functional significance for glutathione status in lymphocytes, since the xc transport system, which is needed to take up cysteine into the cells, is weakly expressed and is inhibited by glutamate, while the neutral amino acid transport system, which takes up cysteine, is functional. Upon gaining entry to the immune cells, cysteine is rapidly converted to GSH. Flow-cytometric analysis of freshly prepared human peripheral-blood lymphocytes shows that lipoic acid is able to normalize a subpopulation of cells with severely compromised thiol status, rather than increasing the level in all cells above normal values (Sen et al., 1997). Hence lipoic acid may also prove to be a useful clinical agent for restoring cellular GSH concentration in immunocompromised subjects.
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