Radioprotective efficacy and acute toxicity of 5-androstenediol after subcutaneous or oral administration in mice.
We previously showed that one subcutaneous (sc) injection of 5-androstene-3beta,17beta-diol (AED) stimulated the innate immune system in mice and prevented mortality due to hemopoietic suppression after whole-body ionizing irradiation with gamma rays. In the present study, we tested whether there was any significant toxicity in mice that might hinder development of this steroid for human use. There were no indications of toxicity in chemical analyses of serum after sc doses as high as 4000 mg/kg. At this dose, 2 of 54 mice died when given AED alone. When 4800 mg/kg was given orally, no deaths resulted. The only adverse findings attributed to AED administration were 1) a moderate elevation of granulocytes in abdominal organs and fat after sc injections of 320 mg/kg; and 2) occasional wasting of skin over the injection site in female B6D2F1 but not male C3H/HeN mice. Significant weight loss (6%) was observed after sc injections of 320 mg/kg but not 160 or 80 mg/kg. When male C3H/HeN mice were injected sc with AED at doses of 0-200 mg/kg 24 h before whole body gamma-irradiation (9 Gy), a significant improvement in survival was observed at doses as low as 5 mg/kg. Oral administration of AED produced significant survival enhancement at a dose of 1600 mg/kg. We conclude that the radioprotective efficacy of AED is accompanied by low toxicity.
Whitnall
Mark H
MH
Radiation Casualty Management Team, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA. whitnall@afrri.usuhs.mil
Wilhelmsen
Catherine L
CL
McKinney
LuAnn
L
Miner
Venita
V
Seed
Thomas M
TM
Jackson
William E
WE
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000097:blood; D015114:Androstenediol / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007279:Injections, Subcutaneous; D008049:Lipase / Q000097:blood; D051379:Mice; D008809:Mice, Inbred C3H; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D011837:Radiation-Protective Agents; D015114:Androstenediol; D008049:Lipase; D000469:Alkaline Phosphatase; D001663:Bilirubin