Neveux Sarah, Smith Nicole K, Roche Anna, Blough Bruce E, Pathmasiri Wimal, Coffin Allison B
College of Arts and Sciences, Washington State University, Vancouver, WA, 98686, USA.
Camas High School, Camas, WA, 98607, USA.
J Assoc Res Otolaryngol. 2017 Apr;18(2):275-289. doi: 10.1007/s10162-016-0604-6. Epub 2016 Nov 28.
Several drugs, including aminoglycosides and platinum-based chemotherapy agents, are well known for their ototoxic properties. However, FDA-approved drugs are not routinely tested for ototoxicity, so their potential to affect hearing often goes unrecognized. This issue is further compounded for natural products, where there is a lack of FDA oversight and the manufacturer is solely responsible for ensuring the safety of their products. Natural products such as herbal supplements are easily accessible and commonly used in the practice of traditional eastern and alternative medicine. Using the zebrafish lateral line, we screened a natural products library to identify potential ototoxins. We found that the flavonoids quercetin and kaempferol, both from the Gingko biloba plant, demonstrated significant ototoxicity, killing up to 30 % of lateral line hair cells. We then examined a third Ginkgo flavonoid, isorhamnetin, and found similar levels of ototoxicity. After flavonoid treatment, surviving hair cells demonstrated reduced uptake of the vital dye FM 1-43FX, suggesting that the health of the remaining hair cells was compromised. We then asked if these flavonoids enter hair cells through the mechanotransduction channel, which is the site of entry for many known ototoxins. High extracellular calcium or the quinoline derivative E6 berbamine significantly protected hair cells from flavonoid damage, implicating the transduction channel as a site of flavonoid uptake. Since known ototoxins activate cellular stress responses, we asked if reactive oxygen species were necessary for flavonoid ototoxicity. Co-treatment with the antioxidant D-methionine significantly protected hair cells from each flavonoid, suggesting that antioxidant therapy could prevent hair cell loss. How these products affect mammalian hair cells is still an open question and will be the target of future experiments. However, this research demonstrates the potential for ototoxic damage caused by unregulated herbal supplements and suggests that further supplement characterization is warranted.
包括氨基糖苷类和铂类化疗药物在内的几种药物，因其耳毒性而广为人知。然而，美国食品药品监督管理局（FDA）批准的药物通常不会进行耳毒性常规检测，因此它们影响听力的可能性常常未被认识到。对于天然产物而言，这个问题更加复杂，因为缺乏FDA的监管，制造商需独自负责确保其产品的安全性。天然产物如草药补充剂很容易获得，并且在传统东方医学和替代医学实践中常用。我们利用斑马鱼侧线，筛选了一个天然产物库以鉴定潜在的耳毒素。我们发现，来自银杏植物的黄酮类化合物槲皮素和山奈酚表现出显著的耳毒性，可杀死高达30%的侧线毛细胞。然后我们检测了第三种银杏黄酮异鼠李素，发现其耳毒性水平相似。黄酮类化合物处理后，存活的毛细胞对活性染料FM 1-43FX的摄取减少，这表明剩余毛细胞的健康受到了损害。然后我们询问这些黄酮类化合物是否通过机械转导通道进入毛细胞，而机械转导通道是许多已知耳毒素的进入位点。高细胞外钙或喹啉衍生物E6小檗胺可显著保护毛细胞免受黄酮类化合物的损伤，这表明转导通道是黄酮类化合物摄取的位点。由于已知耳毒素会激活细胞应激反应，我们询问活性氧是否是黄酮类化合物耳毒性所必需的。与抗氧化剂D-蛋氨酸共同处理可显著保护毛细胞免受每种黄酮类化合物的损伤，这表明抗氧化疗法可以预防毛细胞损失。这些产品如何影响哺乳动物毛细胞仍是一个悬而未决的问题，将是未来实验的目标。然而，这项研究证明了不受监管的草药补充剂导致耳毒性损伤的可能性，并表明有必要进一步对补充剂进行特性描述。
