Department of Biology, Wilfrid Laurier University, 75 University Ave. W., Waterloo, Ontario N2L 3C5, Canada.
Department of Biology, McMaster University, 1280 Main Street W., Hamilton, Ontario L8S 4K1, Canada.
Environ Sci Technol. 2022 Apr 19;56(8):4970-4979. doi: 10.1021/acs.est.1c07117. Epub 2022 Apr 1.
Invasive sea lampreys in the Laurentian Great Lakes are controlled by applying TFM (3-trifluoromethyl-4-nitrophenol) and niclosamide to streams infested with their larvae. Both agents uncouple oxidative phosphorylation in the mitochondria, but TFM specifically targets lampreys, which have a lower capacity to detoxify the lampricide. Niclosamide lacks specificity and is more potent than TFM. However, its greater potency is poorly understood. We tested the hypothesis that niclosamide is a stronger uncoupler of mitochondrial oxidative phosphorylation than TFM by measuring oxygen consumption rates in isolated liver mitochondria exposed to physiologically relevant concentrations of TFM, niclosamide, or their mixture (100 TFM:1 niclosamide) at environmentally relevant temperatures (7, 13, and 25 °C). Niclosamide increased State 4 respiration and decreased the respiratory control ratio (RCR) at much lower concentrations than TFM. Calculations of the relative EC values, the amount of TFM or niclosamide required to decrease the RCR by 50%, indicated that niclosamide was 40-60 times more potent than TFM. Warmer temperature did not appear to decrease the sensitivity of mitochondria to niclosamide or TFM, as observed in the intact sea lamprey exposed to TFM in warmer waters. We conclude that the extreme sensitivity of mitochondria to niclosamide contributes to its greater in vivo toxicity in the whole animal.
在受海七鳃鳗幼虫侵袭的溪流中，应用 TFM（3-三氟甲基-4-硝基苯酚）和氯硝柳胺可以控制大湖区的入侵性海七鳃鳗。这两种药剂都能使线粒体的氧化磷酸化解偶联，但 TFM 专门针对海七鳃鳗，而海七鳃鳗解毒的能力较低。氯硝柳胺缺乏特异性，比 TFM 更有效。然而，其更强的效力还不太清楚。我们通过测量在生理相关浓度的 TFM、氯硝柳胺或其混合物（100 TFM:1 氯硝柳胺）在环境相关温度（7、13 和 25°C）下暴露的分离肝线粒体中的耗氧量来检验氯硝柳胺是一种比 TFM 更强的线粒体氧化磷酸化解偶联剂的假设。氯硝柳胺在比 TFM 低得多的浓度下增加了状态 4 呼吸并降低了呼吸控制比（RCR）。相对 EC 值的计算，即降低 RCR 所需的 TFM 或氯硝柳胺的量减少 50%，表明氯硝柳胺比 TFM 强 40-60 倍。正如在暴露于 TFM 的完整海七鳃鳗在温暖的水中观察到的那样，较高的温度似乎并没有降低线粒体对氯硝柳胺或 TFM 的敏感性。我们的结论是，线粒体对氯硝柳胺的极端敏感性导致其在整个动物体内的毒性更大。
