The Distribution and Metabolism of the Radiation Protective Agent Aminopropylaminoethyl-Phosphorothioate (WR-2721) in Mice.
Final rept. Jul 67-Jun 72,
ALBERT EINSTEIN MEDICAL CENTER PHILADELPHIA PA RADIATION RESEARCH LAB
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Aminopropylaminoethyl-phosphorothioate WR-2721 is the least toxic and most effective of the phosphorothioate class of radiation protective agents. In order to investigate the mechanism of action of this agent, distribution and metabolism studies were carried out using 35S-labelled WR-2721. In mice given WR-2721 intraperitoneally, tissue analysis showed only the unchanged compound and the protective agent bound to proteins by mixed disulfide bond. Concentration of the latter form correlated best with the time course of protection. Dephosphorylation to yield the thiol form of WR-2721, necessary for mixed disulfide formation on tissue proteins, was best demonstrated in the kidneys, both in vivo and in vitro, but also occurs in other tissues. Preliminary studies with the disulfide and thiol forms of WR-2721, which are less protective and more toxic than the phosphorothioate, suggest that the presence of the phosphate is necessary to mask the sulfhydryl group during transport to the target site. Formation of a mixed disulfide with tissue protein sulfhydryl groups at the target site appears to yield the final necessary condition for radiation protection. Author