title: Enhanced hematopoietic protection from radiation by the combination of genistein and captopril.
abstract: The hematopoietic system is sensitive to radiation injury, and mortality can occur due to blood cell deficiency and stem cell loss. Genistein and the angiotensin converting enzyme (ACE) inhibitor captopril are two agents shown to protect the hematopoietic system from radiation injury. In this study we examined the combination of genistein with captopril for reduction of radiation-induced mortality from hematopoietic damage and the mechanisms of radiation protection. C57BL/6J mice were exposed to 8.25Gy (60)Co total body irradiation (TBI) to evaluate the effects of genistein and captopril alone and in combination on survival, blood cell recovery, hematopoietic progenitor cell recovery, DNA damage, and erythropoietin production. 8.25Gy TBI resulted in 0% survival after 30days in untreated mice. A single subcutaneous injection of genistein administered 24h before TBI resulted in 72% survival. Administration of captopril in the drinking water, from 1h through 30days postirradiation, increased survival to 55%. Genistein plus captopril increased survival to 95%. Enhanced survival was reflected in a reduction of radiation-induced anemia, improved recovery of nucleated bone marrow cells, splenocytes and circulating red blood cells. The drug combination enhanced early recovery of marrow progenitors: erythroid (CFU-E and BFU-E), and myeloid (CFU-GEMM, CFU-GM and CFU-M). Genistein alone and genistein plus captopril protected hematopoietic progenitor cells from radiation-induced micronuclei, while captopril had no effect. Captopril alone and genistein plus captopril, but not genistein alone, suppressed radiation-induced erythropoietin production. These data suggest that genistein and captopril protect the hematopoietic system from radiation injury via independent mechanisms.
authors: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. regina.day@usuhs.edu
authors: R M
authors: RM
authors: Day
authors: T A
authors: TA
authors: Davis
authors: M
authors: M
authors: Barshishat-Kupper
authors: E A
authors: EA
authors: McCart
authors: A J
authors: AJ
authors: Tipton
authors: M R
authors: MR
authors: Landauer
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D002216:Captopril / Q000008:administration & dosage* / Q000009:adverse effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000008:administration & dosage* / Q000009:adverse effects; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014916:Whole-Body Irradiation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011837:Radiation-Protective Agents; D004921:Erythropoietin; D002216:Captopril; D019833:Genistein