Modulation of glutathione conjugation in vivo: how to decrease glutathione conjugation in vivo or in intact cellular systems in vitro.

Glutathione conjugation is involved in detoxification and toxification of a variety of electrophilic substrates. Thus it plays a major role in protection against reactive intermediates. At the same time this conjugation may cause resistance of tumor cells against certain cytostatics. In this review the methods available to decrease glutathione conjugation in vivo are discussed. So far the only in vivo active inhibitors of glutathione S-transferases are ethacrynic acid and a number of glutathione-derived structures; the latter seem very promising for further development. For (chronic) glutathione-depletion, buthionine sulfoximine is most effective, and surprisingly safe in clinical studies. Diethylmaleate can be used for acute depletion. Inhibition of glutathione transferases offers advantages over glutathione depletion as a method of decreasing glutathione conjugation since inhibition may be accomplished without changing the activities of other glutathione-dependent reactions in the cell. However, clinically safe, in vivo effective and isoenzyme-selective glutathione S-transferase inhibitors have not yet been developed.