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Mechanism of the 9803 anti-radiation effect

Author: ZhangLiQun
Tutor: GaoYue；MaZengChun
School: PLA Military Academy of Medical Sciences
Course: Pharmacology
Keywords: ionizing radiation cell cycle oxidation reporter gene EMSA
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 117
Quote: 1
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Abstract

Steroid estrogen is a kind of effective radioprotector which can be taken orally or injected before or after radiation. 9803 is derived from 523 which has high radioprotective function but high side effect such as high estrogen activity. In order to increase its radioprotective function and decrease its estrogen activity, a new compound named 9803 was synthesized based on structure-function relationship. Compared with 523, 3-cyclopentyloxy was reserved and 11β-methoxyl was added at steroid nucleus of the structure of 9803 and 17α-acetenyl was removed. Previous studies in our department showed that advanced administration of 9803 could inhibit the apoptosis of bone marrow and spleen cells of mice by promoting the expression of Bcl-2 and repressing the expression of CD95 which was increased after irradiation; pretreatment of 9803 could improve the clinical symptoms and increase the 30d survival rate of beagle significantly by increasing the number of white cells and neutrophilic granulocyte and stimulating the reproduction of hemopoietic progenitor cells. In this study, the effect of 9803 involved in cell viability, apoptosis, cell cyle of AHH-1(human lymphoblast) and cell cycle related molecules were investigated. Furthermore, the activation of 9803 on estrogen receptors and its effect on antioxidation were also investigated.The results showed that 9803 of 20, 80, 320 nmol/L could reduce the DNA tailmoment which was increased after irradiation. 3.0 Gy 60Coγ-ray induced significant cell cycle arrest, necrosis, apoptosis and reduction of viability. Pretreatment with 9803 for 12h before radiation could increase cell viability and regulate cell cycle, but no obvious effect on cell necrosis and apoptosis. The expression of cell cycle arrest related molecules Rb and MDM2 were increased after 3.0 Gy radiation, but decreased significantly with pretreatment of 9803, moreover, the phosphorylation of Rb was also increased. Results indicated that the regulation of cell cycle and promotion of cell proliferation played important roles in the radioprotective function of 9803.There are two types of estrogen receptors i.e. ERαand ERβ. In this study we used a reporter gene system to investigate the activation effect of 9803 on each receptor. The results showed that 9803 could activate ERαsignificantly with a lowest concentration of 10-8 mol/L compared with control group. The induction fold of 9803 (8) with a concentration of 10-8 mol/L on ERαhad no significant difference compared with that of E2 (10). The induction fold of E2 on ERβwas 10 while 9803 had no induction effect on reporter gene on the concentration of 10-10、10-9、10-8、10-7 mol/L. Nevertheless, we studied the activation of 9803 on ERαby electrophoretic mobility shift assay (EMSA) and the results indicated that the binding effect between ERαand estrogen response element was promoted by 9803 but the promotion was a little weaker than that of E2.Ionizing radiation can induce damage to biomacromolecule directly by energy transfer or indirectly by radicals caused by water radiolysis. In our study we determined the content of MDA in the cell supernatant and in the blood of mice. The results showed that the content of MDA was elevated after irradiation and reduced with the pretreatment of 9803. But neither irradiation nor 9803 had significant effects on the mRNA expression of CAT, SOD1, SOD2 and SOD3.

Mechanism of the 9803 anti-radiation effect

Abstract

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