Mantena S K, Unnikrishnan M K, Joshi Ravi, Radha V, Devi P Uma, Mukherjee T
Department of Pharmacology, College of Pharmaceutical Sciences, Manipal 576119, India.
Mutat Res. 2008 Jan 31;650(1):63-79. doi: 10.1016/j.mrgentox.2007.10.005. Epub 2007 Oct 23.
The radioprotective effect of 5-aminosalicylic acid (5ASA) was investigated in mouse bone marrow. The present study was aimed at investigating the radioprotective effect of pre-irradiation treatment with 5ASA against a range of whole-body lethal (8-11 Gy) and sublethal (1-4 Gy) doses of gamma-radiation (RT) in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 5ASA at a dose of 25mg/kg body weight (b. wt.) 30 min before lethal RT increased survival, giving a dose modification factor (DMF) of 1.08. Injection of 5ASA (25 mg/kg b. wt.) 60 or 30 min before or within 15 min after 3 Gy whole body RT resulted in a significant decrease in the radiation-induced aberrant metaphases, at 24 h post-irradiation. Maximum effect was seen when the drug was administered 30 min before irradiation. 5ASA (25 mg/kg b. wt.) significantly reduced the number of aberrant metaphases and the different types of aberrations at all the radiation doses (1-4 Gy) tested, giving a DMFs of 1.43 for number of aberrant metaphases. 5ASA pretreatment also significantly enhanced the endogenous spleen colonies in mouse exposed to 11 Gy RT. Pretreatment with 5ASA, protected plasmid DNA (pGEM-7Zf) against breakage induced by RT and Fenton reactants. Using nanosecond pulse radiolysis technique, the bimolecular rate constant of the reaction of 5ASA with hydroxyl radical was found to be 6.7x10(9)M(-1)s(-1). The p53 and p21 protein levels of bone marrow and spleen were evaluated to identify the specific molecular mechanisms. Both p53 and p21 increased 24h after 6 Gy irradiation, while treatment with 5ASA inhibited this RT-induced increase. Therefore, the present data suggest that 5ASA pretreatment decreases death caused by RT-induced gastrointestinal and hemopoeitic syndromes. The proposed mechanism of radioprotection by 5ASA is through the inhibition of damage to DNA, lipids, and proteins; and prevention of RT-induced increased expression of p53 and p21.
在小鼠骨髓中研究了5-氨基水杨酸（5ASA）的辐射防护作用。本研究旨在探讨成年瑞士白化小鼠在接受一系列全身致死剂量（8 - 11 Gy）和亚致死剂量（1 - 4 Gy）的γ射线辐射（RT）之前，用5ASA进行预处理的辐射防护效果。通过30天小鼠存活率评估对致死性辐射的防护作用，通过照射后24小时骨髓中的染色体畸变评估对亚致死剂量辐射的防护作用。在致死性RT前30分钟腹腔注射25mg/kg体重（b.wt.）的5ASA可提高存活率，剂量修正因子（DMF）为1.08。在3 Gy全身RT前60或30分钟或照射后15分钟内注射5ASA（25 mg/kg b.wt.），在照射后24小时可使辐射诱导的异常中期显著减少。在照射前30分钟给药时效果最佳。5ASA（25 mg/kg b.wt.）在所有测试的辐射剂量（1 - 4 Gy）下均显著减少异常中期的数量和不同类型的畸变，异常中期数量的DMF为1.43。5ASA预处理还显著增强了接受11 Gy RT的小鼠体内的内源性脾集落。5ASA预处理可保护质粒DNA（pGEM - 7Zf）免受RT和芬顿反应物诱导的断裂。使用纳秒脉冲辐解技术，发现5ASA与羟基自由基反应的双分子速率常数为6.7x10(9)M(-1)s(-1)。评估骨髓和脾脏的p53和p21蛋白水平以确定具体的分子机制。6 Gy照射后24小时p53和p21均增加，而用5ASA治疗可抑制这种RT诱导的增加。因此，目前的数据表明5ASA预处理可降低RT诱导的胃肠道和造血系统综合征导致的死亡。5ASA提出的辐射防护机制是通过抑制对DNA、脂质和蛋白质的损伤；以及预防RT诱导的p53和p21表达增加。
