Mechanisms of synergistic toxicity of the radioprotective agent, WR2721, and 6-hydroxydopamine

WR2721 is a prodrug for a radioprotective thiol which has been proposed for adjunctive use as a free radical scavenger in chemotherapy. When used with oxygen radical generating chemotherapeutic agents in mice, however, WR2721 produces synergistic toxicity rather than attenuation of the toxic effects of such agents. The present paper discusses potential mechanisms for such toxicity. The pathway for glutathione synthesis appeared to be inactivated in mice treated with WR2721. The disulfide metabolite of WR2721 was a potent inactivator of γ-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione synthesis. The inactivation of the enzyme by this compound was similar to that reported for cystamine, known to form a mixed disulfide with a cysteine residue near the glutamic acid binding site of the enzyme. Oxygen radicals not only inactivated the synthetase, as well, but hastened the oxidation of the free thiol metabolite of WR2721 to its corresponding disulfide. (author)