Kim S G, Nam S Y, Kim C W
College of Pharmacy, Duksung Women's University, Seoul, Korea.
Biochem Pharmacol. 1998 May 15;55(10):1585-90. doi: 10.1016/s0006-2952(97)00669-2.
Previous studies in this laboratory have shown that oltipraz (Olt), a chemopreventive agent, enhances radiation(Rad)-inducible glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) expression in the liver. The present study was designed to investigate the in vivo radioprotective effect of Olt in ICR mice exposed to a lethal dose of Rad. The 30-day survival rate of mice irradiated at the dose of 8 Gy was substantially increased to 91% by Olt pretreatment (100 mg/kg/day for 2 days), compared with 48% in animals irradiated alone. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray Rad resulted in hepatocyte degeneration in the surviving animals from Day 1 through Day 22 after irradiation with certain degrees of necrosis observed at early times, whereas Olt treatment provided protection of the liver against irradiation with no hepatic necrosis noted. Mice irradiated at the dose of 8 Gy exhibited time-related decreases in the white blood cell (WBC), red blood cell (RBC), and platelet counts with maximal reduction noted at Day 10. Animals irradiated with Olt treatment showed no difference in peripheral blood cell counts or in the ratio of myeloid to erythroid bone marrow cells, compared with those irradiated alone. Northern RNA blot analysis showed that treatment of mice with Olt at the dose of 100 mg/kg in combination with 8 Gy irradiation resulted in 12-fold increases in hepatic mEH and mGSTA3 mRNA levels at 24-hr post-treatment, whereas mGSTP1 mRNA levels were not altered. The mRNA levels for mEH and mGSTA3 were elevated after exposure of animals to both Olt and 8 Gy-gamma ray to a greater extent than after irradiation alone. The enhanced survival rate (91%) in 8 Gy-irradiated animals after treatment with Olt (100 mg/kg/day for 2 days) was completely reversed by concomitant pretreatment with dexamethasone (Dexa) (0.1 and 1 mg/kg/day for 2 days), a known inhibitor of mEH and GST expression, resulting in a 42% and 28% survival rate, respectively. Mice irradiated after dexamethasone treatment at a dose of 1 mg/kg showed a reduced mean survival time compared with those treated with 0.1 mg/kg of dexamethasone (9 vs 14 days). The current study demonstrates that Olt is effective in increasing the survival rate of mice against ionizing Rad and that protective effects of Olt associated with enhanced expression of mEH and GST genes may represent its radioprotective efficacy.
本实验室之前的研究表明，化学预防剂奥替普拉（Olt）可增强肝脏中辐射诱导的谷胱甘肽S-转移酶（GST）和微粒体环氧化物水解酶（mEH）的表达。本研究旨在调查奥替普拉对接受致死剂量辐射的ICR小鼠的体内辐射防护作用。与仅接受辐射的动物（存活率为48%）相比，经奥替普拉预处理（100 mg/kg/天，共2天）后，接受8 Gy剂量辐射的小鼠30天存活率大幅提高至91%。光学显微镜检查显示，小鼠接受8 Gy的γ射线辐射后，存活动物从辐射后第1天至第22天出现肝细胞变性，早期观察到一定程度的坏死，而奥替普拉治疗可保护肝脏免受辐射，未发现肝坏死。接受8 Gy剂量辐射的小鼠白细胞（WBC）、红细胞（RBC）和血小板计数随时间下降，在第10天降至最低值。与仅接受辐射的动物相比，接受奥替普拉治疗的辐射小鼠外周血细胞计数或骨髓中髓系与红系细胞比例无差异。Northern RNA印迹分析表明，以100 mg/kg的剂量给小鼠注射奥替普拉并联合8 Gy辐射，在治疗后24小时，肝脏mEH和mGSTA3 mRNA水平增加了12倍，而mGSTP1 mRNA水平未改变。动物同时接受奥替普拉和8 Gyγ射线照射后，mEH和mGSTA3的mRNA水平升高幅度大于仅接受辐射后。用奥替普拉（100 mg/kg/天，共2天）治疗后，8 Gy辐射动物的存活率提高至91%，但同时用已知的mEH和GST表达抑制剂地塞米松（Dexa）（0.1和1 mg/kg/天，共2天）预处理可完全逆转这一效果，存活率分别降至42%和28%。与接受0.1 mg/kg地塞米松治疗的小鼠相比，接受1 mg/kg地塞米松治疗后再接受辐射的小鼠平均存活时间缩短（9天对14天）。当前研究表明，奥替普拉可有效提高小鼠对电离辐射的存活率，奥替普拉与mEH和GST基因表达增强相关的保护作用可能代表其辐射防护功效。
