线粒体DNA缺失突变对顺铂耳毒易感作用的影响

摘要

目的：建立大鼠线粒体DNA（mtDNA）缺失突变模型,探讨mtDNA缺失突变对顺铂耳毒易感作用的影响。方法选取Wistar大鼠随机分为实验组和对照组,每组20只。其中实验组大鼠以皮下注射阿霉素（DOX）2 mg／kg体重,每周2次,共3个月,对照组则以生理盐水取代DOX。然后两组均连续腹腔注射顺铂2 mg／kg,共6 d。用药前后测试听觉脑干诱发电位（ABR）阈值,并用PCR技术对大鼠内耳膜迷路mtDNA 4834 bp缺失突变进行检测。结果大鼠内耳组织mtDNA检测发现,实验组有13／20只存在4834 bp片段缺失,而对照组未检测到片段缺失；两组大鼠用顺铂前后,ABR阈值提高,两组均数间差异有统计学意义（P﹤0.05）。结论 DOX可诱导大鼠内耳组织mtDNA缺失突变。大鼠内耳组织mtDNA缺失可增加其对顺铂耳毒作用的敏感性。%Objective To establish an animal model of mitochondrial DNA (mtDNA) deletion mutantion and to investi-gate the influence of mtDNA deletion mutantion on the ototoxicity susceptibility role of cisplatin. Methods Wistar rats were randomly divided into experimental group and control group,and there were 20 rats in each group.Doxorubicin (DOX) was subcutaneously injected at dose of 2 mg/kg twice per week for 3 months in experimental group.Control group was identical to experimental group,except normal saline was substituted for DOX.Cisplatin was intraperitoneally injected 2 mg/kg per day for 6 consecutive days in both groups.Auditory brainstem response (ABR) threshold was tested and 4834 bp deletion mutantion of mtDNA in inner ear membranous labyrinth for rats was tested by PCR technique. Results In experimental group,13 of the 20 rats were demonstrated 4834 bp mtDNA deletion,while control group was negative.ABR threshold was improved before and after cisplatin used in rats,and there was a statistical difference of mean between two groups (P﹤0.05). Conclusion In the inner ear tissue of the rat,DOX can induce mtDNA deletion mutantion.mtDNA deletion of the inner ear tissue of the rat can increase its sensitivity of ototoxicity role of cisplatin.