Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice.

We compared in vivo radioprotective efficacy of 5-androstenediol (5-AED) to that of ten other steroids: 17alpha-androstenediol, dehydroepiandrosterone, 5-androstenetriol (AET), 4-androstenedione (AND), testosterone, estradiol, fluasterone, 16alpha-bromoepiandrosterone, 16alpha-fluoro-androst-5-en-17alpha-ol (alpha-fluorohydrin, AFH), and 16alpha-fluoro-androst-5-en-17beta-ol (beta-fluorohydrin). Steroids were administered 24 or 48 hr before, or 1 hr after, whole-body gamma-irradiation. Two days after irradiation at 3 Gy, blood elements were counted. In addition, after irradiation at 9-12.5 Gy, survival was recorded for 30 days. The results showed radioprotective efficacy was specific for 5-AED. One other steroid, AFH, demonstrated appreciable survival effects but was less efficacious than 5-AED. AND and AET produced slight enhancement of survival in some experiments. This is the first demonstration that the prophylactic window for survival enhancement by 1 subcutaneous (s.c.) injection of 5-AED is as long as 48 hr in mice. Moreover, the results indicate that 1 s.c. injection of 5-AED 1 hr after irradiation is much less effective than 1 injection 24-48 hr before irradiation. Comparing the molecular features of steroids with radioprotective efficacy leads to the following conclusions: 1) these effects are due to interaction with specific receptors, since s.c. injection of extremely similar molecules with the same physicochemical properties as 5-AED were not radioprotective; 2) the 17-hydroxyl group is essential; 3) this group must be in the beta configuration in the absence of nearby side groups; 4) a halogen atom at 16 changes the 17-hydroxyl specificity to alpha; 5) the 3beta-hydroxyl group is not essential; 6) addition of a 7beta-hydroxyl group is deleterious; and 7) the effects are not due to activation of sex steroid receptors.

New strategies for the prevention of radiation injury: possible implications for countering radiation hazards of long-term space travel.

New strategies for the prevention of radiation injuries are currently being explored with the ultimate aim of developing globally radioprotective, nontoxic pharmacologics. The prophylactic treatments under review encompass such diverse pharmacologic classes as novel immunomodulators, nutritional antioxidants, and cytokines. An immunomodulator that shows promise is 5-androstenediol (AED), a well-tolerated, long-acting androstene steroid with broad-spectrum radioprotective attributes that include not only protection against acute tissue injury, but also reduced susceptibility to infectious agents, as well as reduced rates of neoplastic transformation. Other potentially useful radioprotectants currently under study include the nutraceutical vitamin E and analogs, a chemically-engineered cytokine, interleukin-1beta, and a sustained-release formulation of an aminothiol, amifostine. Results suggest that a new paradigm is evolving for the prophylaxes of radiation injuries, based on use of newly identified, nontoxic, broad-spectrum prophylactic agents whose protective action may be leveraged by subsequent postexposure use of cytokines with organ-specific reparative functions.