On the mode of action of x-ray protective agents. I. The fixation in vivo of cystamine and cysteamine to proteins.

Several hypotheses have been advanced in attempts to account for the ability of certain thiol (SH)or disulfide (SS)-containing compounds to reduce the biological lesions caused by ionizing radiation (1, 2). It is clear that, in pure aqueous solutions, radiochemical transformations are for the greater part mediated by products formed by the interaction of ionizing radiation with water molecules (3). At the present time the favored hypothesis seems to be that these protective agents exert their action by reducing the number of radiation-induced free radicals (1, 2, 4). HOWever, we have recently found that when cystamine, one of the most potent protective agents (5, S), is present in a biological medium, its ability to inactivate free radicals is far too low to account for its protective ability in viva (7). A reinvestigation of the detailed biochemistry of cystamine was therefore deemed desirable. In the present paper, the metabolism of sulfur-labeled cystamine and cysteamine has been studied by means of methods which permitted the detection of lo-’ mg. of cystamine or cysteamine sulfur. It has been established that, after intraperitoneal administration of protective doses to mice, by far the greater part of the cystamine or cysteamine occurs in chemical combination with proteins and other constituents in serum and in the red cells. During the period of optimal protection only a minor fraction of cystamine or cysteamine is present in free form. It is suggested that this extensive, but temporary, binding of cystamine or cysteamine to tissue constituents is causally related to the protective ability of these compounds. Evidence is presented that the fixation is due to the formation of mixed disulfides between cysteamine and the SH groups of body constituents, a phenomenon which appears to be of general biochemical interest.