Oxidative stress pathways in the potentiation of noise-induced hearing loss by acrylonitrile
Oxidative stress pathways in the potentiation of noise-induced hearing loss by acrylonitrile
复制标题
DOI：
10.1016/j.heares.2006.11.009
复制
发表时间：
2007-02-01
期刊：
影响因子：
2.8
通讯作者：
Fechter, Laurence
中科院分区：
文献类型：
--
作者：
Pouyatos, Benoit;Gearhart, Caroline;Fechter, Laurence
我们假设抗氧化防御系统的破坏是化学污染物增强噪声性听力损失（NIHL）的关键机制。使用丙烯腈（ACN）测试了这一假设，丙烯腈是一种广泛使用的工业化学品，其代谢与谷胱甘肽（GSH）消耗和氰化物（CN）生成有关。CN对Cu/Zn超氧化物歧化酶（SOD）有抑制作用。我们以前已经表明，ACN增强NIHL，即使噪声暴露接近允许的职业水平。然而，GSH消耗和/或CN生产在这种增强的相对参与仍然是未知的。在这项研究中，我们改变了这些代谢途径，以进一步阐明特定的抗氧化剂在保护耳蜗中的作用。我们研究了硫代硫酸钠（STS）（CN抑制剂）、4-甲基吡唑（4 MP）（一种通过与CYP 2 E1竞争阻断CN生成的药物）和L-N-乙酰半胱氨酸（L-NAC）（一种促GSH药物）的作用，以区分GSH耗竭和CN生成作为ACN增强NIHL的机制。Long-Evans大鼠暴露于倍频程噪声（97 dB SPL，4 h/d，5 d）和ACN（50 mg/kg）。STS（150 mg/kg）、4 MP（100 mg/kg）和L-NAC（4 x 400 mg/kg）单独预处理均显著降低血液CN水平，但只有L-NAC显著保护肝脏和耳蜗中的GSH水平。同时，只有L-NAC治疗减少了由ACN +噪声引起的听觉损失和毛细胞损失，表明GSH参与保护耳蜗免受中等噪声水平产生的活性氧的影响。另一方面，CN似乎不参与这种增强作用。由爱思唯尔公司出版
We hypothesize that the disruption of antioxidant defenses is a key mechanism whereby chemical contaminants can potentiate noise-induced hearing loss (NIHL). This hypothesis was tested using acrylonitrile (ACN), a widely used industrial chemical whose metabolism is associated with glutathione (GSH) depletion and cyanide (CN) generation. CN, in turn, can inhibit Cu/Zn superoxide dismutase (SOD). We have shown previously that ACN potentiates NIHL, even with noise exposure approaching permissible occupational levels. However, the relative involvement of GSH depletion and/or CN production in this potentiation is still unknown. In this study, we altered these metabolic pathways pharmacologically in order to further delineate the role of specific antioxidants in the protection of the cochlea. We investigated the effects of sodium thiosulfate (STS), a CN inhibitor, 4-methylpyrazole (4MP), a drug that blocks CN generation by competing with CYP2E1, and L-N-acetylcysteine (L-NAC), a pro-GSH drug, in order to distinguish between GSH depletion and CN production as the mechanism responsible for potentiation of NIHL by ACN. Long-Evans rats were exposed to an octave-band noise (97 dB SPL, 4 h/day, 5 days) and ACN (50 mg/kg). Separate pre-treatments with STS (150 mg/kg), 4MP (100 mg/kg) and L-NAC (4 x 400 mg/kg) all dramatically reduced blood CN levels, but Only L-NAC significantly protected GSH levels in both the liver and the cochlea. Concurrently, only L-NAC treatment decreased the auditory loss and hair cell loss resulting from ACN + noise, suggesting that GSH is involved in the protection of the cochlea against reactive oxygen species generated by moderate noise levels. On the other hand, CN does not seem to be involved in this potentiation. Published by Elsevier B.V.