百草枯的全身毒性及特异性耳毒性作用  

Systemic Toxicity and Specific Ototoxicity of Paraquat

作　　者：张建辉 丁大连[1,2] 孙虹[1,2] Richard Salvi 

机构地区：[1]中南大学附属湘雅医院耳鼻咽喉头颈外科 [2]Center for Hearing and Deafness, University at Buffalo [3]川北医学院附属医院耳鼻咽喉头颈外科

出　　处：《中华耳科学杂志》2017年第4期481-488,共8页Chinese Journal of Otology

基　　金："973"国家重大科学研究计划项目(2014CB943003);国家自然科学基金面上项目(81170912)~~

摘　　要：百草枯是目前全球使用最广泛的除草剂之一,其对哺乳类生物体的毒性机制主要是在细胞内通过反复氧化还原反应而产生大量的过氧化物阴离子并引发脂质过氧化、线粒体损伤、DNA损害、蛋白质破坏,最终导致细胞凋亡等级联反应造成全身多器官的不可逆性损害。百草枯在急性中毒过程往往在肺泡细胞首先表现出特殊的高浓度聚集,这可能是因为百草枯与多胺的化学结构相似,而肺的Clara细胞和肺泡I型及II型上皮细胞具备较强的多胺转运系统,因此百草枯首先积聚在肺的Clara细胞和肺泡I型及II型细胞。百草枯还可穿越血脑屏障并通过多巴胺转运系统在多巴胺神经元中积累并首先造成多巴胺神经元的破坏,因此,百草枯慢性中毒可能与帕金森病的发病机制也具有一定的关系。各种耳毒性药物和强噪声以及重金属和老年性耳聋引起的内耳损伤都与氧自由基的损害作用密切相关,百草枯对细胞的氧化损伤作用使之成为研究内耳自由基损害和抗氧化剂保护效应的理想研究模型之一。百草枯引起的实验动物听觉障碍表现出高频听力首先受损的特点,百草枯引起的耳蜗毛细胞损害则首先发生在耳蜗底回对应高频听觉反应的区域。在百草枯引起的受损耳蜗细胞内,过氧化物阴离子首先在细胞质中的表达增强,随后凝聚到细胞核内,说明耳蜗细胞的损害确实是因为细胞内首先发生的氧化应激所引起,而这种自由基损害最终启动了细胞的自毁装置而导致了细胞的凋亡。我们在最近的实验研究中发现,百草枯对耳蜗细胞的损害首先是发生在耳蜗毛细胞底部和周围的支持细胞,由于这些支持细胞的破坏造成耳蜗Corti器的支持结构塌陷,从而使耳蜗毛细胞因失去周围细胞的连接和支持而发生排列散乱和位置漂移,这种因失去细胞之间的联系而发生的毛细胞"失巢凋亡"可能也是造�Paraquat（PQ）, one of the most widely used herbicides in the world, is believe to exert its toxic effects on mammalian organisms by generating a large amount of superoxides via redox reactions which in turn cause lipid peroxidation, mitochondrial degeneration, DNA damage and protein degradation. In the acute poisoning process, PQ initially accumulates in alveolar cells in the lungs presumably because the chemical structure of PQ is similar to polyamine.Clara cells and alveolar type I and II epithelial cells in the lungs contain very strong polyamine transport systems. PQ can also cross the blood-brain barrier and accumulate in dopaminergic neurons by uptake through dopamine transporters making, dopaminergic neurons highly susceptible to PQ neurotoxicity. Consequently, chronic PQ poisoning has been implicated in the pathogenesis of Parkinson＇s disease. PQ has also been shown to damage sensory hair cells in the cochlea. The damage is thought to be mediated by increased production of superoxide anions and oxidative stress. Local application of PQ induces a stereotypic pattern of damage which begins at the base of the cochlea and progresses toward the apex, consistent with early high-frequency hearing loss that expands to low frequencies. In PQ damaged cochlear cells, superoxide anions detected by dihydroethidium first appear in the cytoplasm and later condense in the nucleus,suggesting that the damage to cochlear cells is indeed due to the occurrence of superoxide. The free radical damage eventually initiates the cell＇s self-destruction leading to apoptosis. In contrast to earlier reports, our recent experimental studies indicate that PQ-induced cochlear cell damage first occurs in supporting cells. The destruction of these support cells results in the collapse of support structures of the organ of Corti such that cochlear hair cells become detached and rearranged within the sensory epithelium. Anoikis is a form of programmed cell death that is induced by anchorage-dependent cells becoming detached from the s

关 键 词：百草枯 耳毒性 氧化应激 耳蜗 失巢凋亡 

分 类 号：R764[医药卫生—耳鼻咽喉科]