Institute of Oceanography and Fisheries, Split, Croatia
University Department of Marine Studies, University of Split, Split, Croatia.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00916-18. Print 2018 Sep.
Anisakiasis is among the most significant emerging foodborne parasitoses contracted through consumption of thermally unprocessed seafood harboring infective species larvae. The efficacy of the currently applied anthelminthic therapy in humans and in model organisms has not proven sufficient, so alternative solutions employing natural compounds combined with chemical inhibitors should be explored. By testing toxicity of the natural monoterpenes nerolidol and farnesol and the conventional anthelminthics abamectin and levamisole in the presence/absence of MK-571 and Valspodar, which inhibit the ABC transporter proteins multidrug resistance protein (MRP-like) and P-glycoprotein (P-gp), we determined the preliminary traits of detoxifying mechanisms. We found that P-gp and MRP-like transporters have a role in the efflux of the tested compounds, which could be useful in the design of novel anthelminthic strategies. As expected, transporter activation and efflux fluctuated over time; they were synchronously active very early postexposure, whereas the activity of one transporter dominated over the other in a time-dependent manner. MRP-like transporters dominated in the efflux of farnesol, and P-gp dominated in efflux of nerolidol, while both were active in effluxing levamisole. The highest toxicity was exerted by abamectin, a P-gp inhibitor , which also elicited the highest oxidative stress in treated larvae. We suggest that β-tubulin, observed for the first time as a core element in cuticle, might represent an important target for the tested compounds.
旋毛虫病是最主要的食源性寄生虫病之一，通过食用未经过热处理的含有感染性幼虫的海鲜而感染。目前应用于人类和模式生物的驱虫疗法的疗效并不理想，因此应该探索使用天然化合物结合化学抑制剂的替代解决方案。通过在存在/不存在 MK-571 和 Valspodar 的情况下测试天然单萜橙花叔醇和法呢醇以及常规驱虫药阿维菌素和左旋咪唑的毒性，我们确定了初步的解毒机制特征。我们发现 P-糖蛋白 (P-gp) 和多药耐药相关蛋白样 (MRP-like) 转运蛋白在测试化合物的外排中起作用，这可能有助于设计新的驱虫策略。正如预期的那样，转运蛋白的激活和外排随时间波动；它们在暴露后非常早期同步活跃，而一种转运蛋白的活性在时间上超过另一种。MRP-like 转运蛋白在法呢醇的外排中起主导作用，P-gp 在橙花叔醇的外排中起主导作用，而两者都在左旋咪唑的外排中起作用。阿维菌素（一种 P-gp 抑制剂）的毒性最高，它还在处理过的幼虫中引起最高的氧化应激。我们认为，β-微管蛋白首次被观察到作为表皮的核心元素，可能是测试化合物的一个重要靶标。
