2个双硫仑衍生物对小鼠的辐射防护作用

Radiation protective effects of two disulfiram derivatives in mice

    摘要
  • 摘要:
    目的  研究2个双硫仑（DSF）衍生物对小鼠的辐射防护作用。
    方法  采用两步合成法制备了2个双硫仑衍生物DSF-1和DSF-2进行小鼠辐射防护实验。在致死剂量照射（7.2 Gy 137Cs γ射线全身照射）小鼠实验中，采用随机区组设计，将50只C57BL/6J雄性小鼠分为5组，分别为对照组、致死剂量照射组（IR1组）、DSF灌胃给药（DSFi.g.）+IR1组、DSF-1灌胃给药（DSF-1i.g）+IR1组、DSF-2灌胃给药（DSF-2i.g.）+IR1组，每组10只；将40只C57BL/6J雄性小鼠分为4组，分别为对照组、IR1组、DSF腹腔注射给药（DSFi.p.）+IR1组、DSF-2腹腔注射给药（DSF-2i.p.）+IR1组，每组10只。计算每组小鼠的生存率及保护指数在亚致死剂量照射（6.0 Gy 137Cs γ射线全身照射）小鼠实验中，采用随机区组设计，将24只C57BL/6J雄性小鼠分为4组，分别为亚致死剂量照射组（IR2组）、DSFi.g.+IR2组、DSF-1i.g.+IR2组及DSF-2i.g.+IR2组，每组6只；将18只C57BL/6J雄性小鼠分为3组，分别为IR2组、DSFi.p.+IR2组、DSF-2i.p.+IR2组，每组6只。计算小鼠的脏器指数，检测造血、免疫系统及抗氧化损伤指标。照射给药组剂量均为50 mg/kg，对照组和照射组（IR1组、IR2组）给予等量溶剂（0.5%的羧甲基纤维素钠溶液），照射前均连续给药3天。计量资料的组间比较采用t检验（方差齐）。采用Kaplan-Meier法绘制累计生存率曲线。
    结果 经化合物鉴定，成功合成了2个目标化合物DSF-1和DSF-2。致死剂量照射小鼠实验结果显示，与IR1组相比，DSF-1i.g.+IR1组和DSF-2i.g.+IR1组小鼠的30 d生存率均提高50%，差异均有统计学意义（22.0±8.7） d对 （9.9±2.0） d、（22.0±8.5） d 对（9.9±2.0） d；t=3.91、4.03，P=0.003、0.002； DSF-2i.p.+IR1组小鼠的30 d生存率提高60%，差异有统计学意义（25.4±7.8） d 对（18.6±6.6） d；t=2.16，P=0.045）。亚致死剂量照射小鼠实验结果显示，与IR2组相比，DSF-1i.g.+IR2组和DSF-2i.g.+IR2组小鼠的胸腺指数均提高，差异均有统计学意义（2.42±0.48） mg/g对（1.60±0.25） mg/g、（2.28±0.33） mg/g对（1.60±0.25） mg/g，t=3.30、3.57，P=0.017、0.009；DSF-2i.g.+IR2组受照小鼠的性腺指数、脾集落形成单位（CFU-S）数及外周血白细胞（WBC）数提高，差异均有统计学意义（27.42±1.64） mg/g对（23.54±2.72） mg/g、（15.42±4.01）个对（5.69±6.28）个、（0.99±0.12）×109/L对（0.61±0.12）×109/L，t=2.92、3.17、5.30，均P<0.05）；DSF-2i.p.+IR2组小鼠的胸腺指数、脾指数、骨髓有核细胞数、CFU-S数及WBC数提高，差异均有统计学意义（2.23±0.48） mg/g对（1.69±0.09） mg/g、（1.23±0.21） mg/g对（0.95±0.16） mg/g、（7.09±3.33）106/根股骨对（3.09±0.78）106/根股骨、（6.27±2.38）个对（2.34±0.62）个、（0.32±0.12）×109/L对（0.18±0.03）×109/L，t=2.60~3.60，均P<0.05）；DSF-1i.g.+IR2组小鼠肝脏的GSH含量提高，差异有统计学意义（48.79±6.01） μmol/gprot对（37.49±4.33） μmol/gprot，t=3.28，P=0.014）；DSF-2i.p.+IR2组小鼠肝脏MDA含量降低，差异有统计学意义（0.63±0.52） nmol/gprot对（1.74±0.34） nmol/gprot，t=3.67，P=0.014）。
    结论  2个双硫仑衍生物DSF-1和DSF-2对小鼠具有明显的辐射防护效果，有希望进一步开发作为辐射防护药物。

     

    Abstract:
    Objective  To explore the radiation protection of disulfiram (DSF) derivatives in mice.
    Methods  Two DSF derivatives (DSF-1 and DSF-2) were synthesized using a two-step synthesis method and tested for radiation protection in mice. In the lethal dose irradiation experiment (7.2 Gy 137Cs γ-ray whole-body irradiation), 50 male C57BL/6J mice were randomly divided into five groups (n=10): control group, lethal dose irradiation (IR1) group, DSF oral administration (DSFi.g.)+IR1 group, DSF-1 oral administration (DSF-1i.g.)+IR1 group, and DSF-2 oral administration (DSF-2i.g.)+IR1 group. Another 40 male C57BL/6J mice were randomly divided into four groups (n=10): control group, IR1 group, DSF intraperitoneal injection (DSFi.p.)+IR1 group, and DSF-2 intraperitoneal injection (DSF-2i.p.)+IR1 group. Survival rates and protective index were calculated for each group. In the sublethal dose irradiation experiment (6.0 Gy 137Cs γ-ray whole-body irradiation), 24 male C57BL/6J mice were randomly divided into four groups (n=6): sublethal irradiation group (IR2), DSFi.g.+IR2 group, DSF-1i.g.+IR2 group, and DSF-2i.g.+IR2 group. Another 18 male C57BL/6J mice were randomly divided into three groups (n=6): IR2 group, DSFi.p.+IR2 group, and DSF-2i.p.+IR2 group. Organ index, hematopoietic, immune system, and antioxidant damage indicators were evaluated. The treatment groups received 50 mg/kg of DSF derivatives, and the control and irradiation groups (IR1 group and IR2 group) received equivalent solvent volumes (0.5% sodium carboxymethyl cellulose solution) for 3 days before irradiation. t-tests were used for comparing data (equal variance), and Kaplan–Meier curves were used for survival rates.
    Results  DSF-1 and DSF-2 were successfully synthesized and identified. In the lethal dose irradiation experiment, the DSF-1i.g.+IR1 group and DSF-2i.g.+IR1 group showed 50% increase in the 30-day survival rate compared with the IR1 group, with statistically significant differences (22.0±8.7) d vs. (9.9±2.0) d, (22.0±8.5) d vs. (9.9±2.0) d; t=3.91, 4.03; P=0.003, 0.002. The DSF-2i.p.+IR1 group showed a 60% increase in 30-day survival, with a statistically significant difference (25.4±7.8) d vs. (18.6±6.6) d; t=2.16, P=0.045. In the sublethal dose irradiation experiment, the thymus index of the DSF-1i.g.+IR2 and DSF-2i.g.+IR2 groups increased significantly compared with that of the IR2 group (2.42±0.48) mg/g vs. (1.60±0.25) mg/g, (2.28±0.33) mg/g vs. (1.60±0.25) mg/g; t=3.30, 3.57; P=0.017, 0.009. The DSF-2i.g.+IR2 group showed significantly increased gonad index, colony forming unit-spleen (CFU-S) count, and peripheral white blood cell (WBC) count compared with the IR2 group (27.42±1.64) mg/g vs. (23.54±2.72) mg/g, (15.42±4.01) vs. (5.69±6.28), (0.99±0.12)×109/L vs. (0.61±0.12)×109/L; t=2.92, 3.17, 5.30; all P<0.05. The DSF-2i.p.+IR2 group demonstrated a significant increase in thymus index, spleen index, bone marrow nucleated cell count, CFU-S count, and WBC count compared with the IR2 group (2.23±0.48) mg/g vs. (1.69±0.09) mg/g, (1.23±0.21) mg/g vs. (0.95±0.16) mg/g, (7.09±3.33)×106/femur vs. (3.09±0.78)×106/femur, (6.27±2.38) vs. (2.34±0.62), (0.32±0.12)×109/L vs. (0.18±0.03)×109/L; t=2.60–3.60, all P<0.05. The DSF-1i.g.+IR2 group exhibited a significant increase in liver glutathione content (48.79±6.01) μmol/gprot vs. (37.49±4.33) μmol/gprot; t=3.28, P=0.014, and the DSF-2i.p.+IR2 group had a significantly decreased liver malondialdehyde content (0.63±0.52) nmol/gprot vs. (1.74±0.34) nmol/gprot; t=3.67, P=0.014.
    Conclusion  The two DSF derivatives, DSF-1 and DSF-2, demonstrate significant radiation protective effects in mice and hold promise for further development as radioprotectant.

     

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