Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy

Abstract

Glutathione, which is synthesized within cells, is a component of a pathway that uses NADPH to provide cells with their reducing milieu. This is essential for (a) maintenance of the thiols of proteins (and other compounds) and of antioxidants (e.g. ascorbate, alpha-tocopherol), (b) reduction of ribonucleotides to form the deoxyribonucleotide precursors of DNA, and (c) protection against oxidative damage, free radical damage, and other types of toxicity. Glutathione interacts with a wide variety of drugs. Despite its many and varied cellular functions, it is possible to achieve therapeutically useful modulations of glutathione metabolism. This article emphasizes an approach in which the synthesis of glutathione is selectively inhibited in vivo leading to glutathione deficiency. This is achieved through use of transition-state inactivators of gamma-glutamylcysteine synthetase, the enzyme that catalyzes the first and rate-limiting step of glutathione synthesis. The effects of marked glutathione deficiency, thus produced in the absence of applied stress, include cellular damage associated with severe mitochondrial degeneration in a number of tissues. Such glutathione deficiency is not prevented or reversed by giving glutathione. The cellular utilization of GSH involves its extracellular degradation, uptake of products, and intracellular synthesis of GSH. This is a normal pathway by which cysteine moieties are taken up by cells. Glutathione deficiency induced by inhibition of its synthesis may be prevented or reversed by administration of glutathione esters which, in contrast to glutathione, are readily transported into cells and hydrolyzed to form glutathione intracellularly. Research derived from this model has led to several potentially useful therapeutic approaches, one of which is currently in clinical trial. Thus, certain tumors, including those that exhibit resistance to several drugs and to radiation, are sensitized to these modalities by selective inhibition of glutathione synthesis. An alternative interpretation is suggested which is based on the concept that some resistant tumors have high capacity for glutathione synthesis and that such increased capacity may be as significant or more significant in promoting the resistance of some tumors than the cellular levels of glutathione. Therapeutic approaches are proposed in which normal cells may be selectively protected against toxic antitumor agents and radiation by cysteine- and glutathione-delivery compounds. Current studies suggest that research on other modulations of glutathione metabolism and transport would be of interest.