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多柔比星耳毒性的实验研究
引用本文:韩月臣,孔维佳,胡钰娟,王莹,刘俊,王琼.多柔比星耳毒性的实验研究[J].中国药学杂志,2005,40(3):196-199.
作者姓名:韩月臣  孔维佳  胡钰娟  王莹  刘俊  王琼
作者单位:华中科技大学同济医学院附属协和医院耳鼻咽喉科,湖北,武汉,430022
基金项目:国家自然科学基金,国家自然科学基金,高等学校博士学科点专项科研项目,高等院校骨干教师基金
摘    要: 目的 探讨多柔比星的耳毒性及维生素E(VitE)和泛癸利酮(CoQ10)的保护作用。方法 Wistar大鼠46只,随机分为3组,其中A组大鼠18只,腹腔注射多柔比星(doxorubicin,DOX)1mg·kg-1(体重),每周2次,同时给予生理盐水灌胃,共3个月;B组大鼠18只,腹腔注射多柔比星1mg·kg-1(体重),每周2次,共3个月,同时给予CoQ10 10mg·kg-1·d-1和VitE50mg·kg-1·d-1灌胃;C组大鼠10只,全程以等量生理盐水替代进行腹腔注射及灌胃。用药前后分别进行听性脑干反应(ABR)检测。提取耳蜗组织总DNA,利用巢式聚合酶链式反应(nestedPCR)检测线粒体DNA4834bp缺失突变的发生情况,PCR产物直接测序。同时测定血清谷光苷肽过氧化物酶活性。结果 B组用药后听阈增高(9.23±19.01)dB较A组(20.94±16.24)dB低,差异有极显著性意义(P<0.01);B组和C组相比听阈增高,差异无显著性意义;B组内耳组织线粒体DNA4834缺失突变发生率(23.08%)较A组(68.75%)明显降低,差异有显著性意义(P<0.05);B组血清谷光苷肽过氧化物酶活性(140.94±42.58)U比A组(59.95±18.65)U高,差异有极显著性意义(P<0.01)。结论 长期应用多柔比星可引起大鼠听阈的轻度增高,诱发内耳组织线粒体DNA4834bp缺失突变。CoQ10和VitE可以降低多柔比星对内耳组织的损伤作用。

关 键 词:多柔比星  线粒体DNA  突变  耳毒性
文章编号:1001-2494(2005)03-0196-04
收稿时间:2004-02-04;

Experimental study on ototoxicity of doxorubicin in rats
HAN Yue-chen,KONG Wei-jia,HU Yu-juan,WANG Ying,LIU Jun,WANG Qiong.Experimental study on ototoxicity of doxorubicin in rats[J].Chinese Pharmaceutical Journal,2005,40(3):196-199.
Authors:HAN Yue-chen  KONG Wei-jia  HU Yu-juan  WANG Ying  LIU Jun  WANG Qiong
Affiliation:HAN Yue-chen,KONG Wei-jia*,HU Yu-juan,WANG Ying,LIU Jun,WANG Qiong
Abstract:OBJECTIVE To investigate the ototoxicity of doxorubicin(DOX) and the protective roles of vitamin E and Coenzyme Q10. METHODS 46 Wistar rats were randomly divided into 3 groups. There were 18 rats in group A and group B respectively, and 10 rats in group C. The rats in group A and group B were given doxorubicin by intraperitoneal injection twice a week for 3 months, At the same time the rats in group B took vitamin E 50 mg·kg-1·d-1 and CoQ10 10 mg·kg-1·d-1 orally but the rats in group A were given saline instead. Group C received only saline. The auditory threshold was measured before and after the drug administrations by auditory brainstem respons (ABR). The inner ear tissues were harvested, and then the mitochondrial DNA was amplified to identify the 4834bp deletion mutation of mitochondrial DNA by nested-primer PCR. The products of PCR were verified by sequencing. The activity of glutathione peroxidase of serum was measured.RESULTS The auditory threshold elevation of group B(9.23±19.01)dB was significant lower than that of group A(20.94±16.24)dB(P<0.05). There was no significant difference between group B and group C.The incidence of mitochondrial DNA 4834bp deletion mutation of group B (23.08%) was significant lower than that of group A (68.75%) (P<0.01). The activity of serum glutathione peroxidase of group B (140.94±42.58)U was markedly higher than that of group A (59.95±18.65)U (P<0.05). CONCLUSION The results suggested that long-term DOX therapy could raise the auditory threshold slightly and induce the 4834bp deletion mutation of mitochondrial DNA of rat. Vitamin E and CoQ10 could markedly inhibit this kind of ototoxicity of DOX.
Keywords:doxorubicin  mitochondrial DNA  mutation  ototoxicity
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