Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster
Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster
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DOI：
10.1038/s41598-018-20720-7
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发表时间：
2018-02-05
影响因子：
4.6
通讯作者：
Perouansky, Misha
中科院分区：
文献类型：
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作者：
Olufs, Zachariah P. G.;Loewen, Carin A.;Perouansky, Misha
遗传可变性影响对多种外源药物的反应，但其在临床上观察到的对全身麻醉药的异常反应中的作用仍不确定。为了研究挥发性全身麻醉剂(VGA)的药物遗传学，我们研制了一套连续麻醉阵列装置，将多只黑腹果蝇样本暴露于VGA，并进行了行为学分析，以确定VGA的药代动力学和药效学性质。我们研究了来自果蝇遗传参考室的四个野生型菌株、两个常用的实验室菌株(广州S和W(1118))和一个线粒体电子传递链复合体I的突变体(ND23(60114))中的VGA异氟烷和七氟醚。在所有七个菌株中，异氟醚的效力比七氟烷强，从它们的相对脂溶解度预测，异氟烷的出现比七氟烷慢，在哺乳动物中再现了主要的药代动力学和药效学特性。此外，ND23(60114)果蝇对这两种药物更敏感，正如在携带复杂I基因突变的蠕虫、小鼠和人类中观察到的那样。此外，我们发现果蝇品系之间在异氟醚和七氟醚的绝对和相对药代动力学和药效学曲线上都有很大的差异。这些数据表明，自然发生的遗传变异对VGA的基本药理特性有可测量的影响，苍蝇可用于识别相关的遗传变异。
Genetic variability affects the response to numerous xenobiotics but its role in the clinically-observed irregular responses to general anesthetics remains uncertain. To investigate the pharmacogenetics of volatile general anesthetics (VGAs), we developed a Serial Anesthesia Array apparatus to expose multiple Drosophila melanogaster samples to VGAs and behavioral assays to determine pharmacokinetic and pharmacodynamic properties of VGAs. We studied the VGAs isoflurane and sevoflurane in four wild type strains from the Drosophila Genetic Reference Panel, two commonly used laboratory strains (Canton S and w(1118)), and a mutant in Complex I of the mitochondrial electron transport chain (ND23(60114)). In all seven strains, isoflurane was more potent than sevoflurane, as predicted by their relative lipid solubilities, and emergence from isoflurane was slower than from sevoflurane, reproducing cardinal pharmacokinetic and pharmacodynamic properties in mammals. In addition, ND23(60114) flies were more sensitive to both agents, as observed in worms, mice, and humans carrying Complex I mutations. Moreover, we found substantial variability among the fly strains both in absolute and in relative pharmacokinetic and pharmacodynamic profiles of isoflurane and sevoflurane. These data indicate that naturally occurring genetic variations measurably influence cardinal pharmacologic properties of VGAs and that flies can be used to identify relevant genetic variations.