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首页> 外文期刊>Journal of Cellular Physiology >Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system.
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Lipophilic cationic drugs increase the permeability of lysosomal membranes in a cell culture system.

机译：亲脂性的阳离子药物增加在细胞中溶酶体膜的渗透性文化系统。

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摘要

Lysosomes accumulate many drugs several fold higher compared to their extracellular concentration. This mechanism is believed to be responsible for many pharmacological effects. So far, uptake and release kinetics are largely unknown and interactions between concomitantly administered drugs often provoke mutual interference. In this study, we addressed these questions in a cell culture model. The molecular mechanism for lysosomal uptake kinetics was analyzed by live cell fluorescence microscopy in SY5Y cells using four drugs (amantadine, amitriptyline, cinnarizine, flavoxate) with different physicochemical properties. Drugs with higher lipophilicity accumulated more extensively within lysosomes, whereas a higher pK(a) value was associated with a more rapid uptake. The drug-induced displacement of LysoTracker was neither caused by elevation of intra-lysosomal pH, nor by increased lysosomal volume. We extended our previously developed numerical single cell model by introducing a dynamic feedback mechanism. The empirical data were in good agreement with the results obtained from the numerical model. The experimental data and results from the numerical model lead to the conclusion that intra-lysosomal accumulation of lipophilic xenobiotics enhances lysosomal membrane permeability. Manipulation of lysosomal membrane permeability might be useful to overcome, for example, multi-drug resistance by altering subcellular drug distribution.
机译：溶酶体积累许多药物几折高于细胞外浓度。负责许多药理作用。吸收和释放动力学主要是未知的,与此同时之间的相互作用管理药物往往会激发相互的干扰。在细胞培养模型的问题。溶酶体吸收动力学机制分析了活细胞荧光显微镜使用四种药物SY5Y细胞(金刚烷胺,阿米替林、桂利嗪flavoxate)不同的物理化学性质。更高的亲油性积累更广泛在溶酶体中,而更高的pK (a)的价值与一个更快速的吸收。药物引起的位移LysoTracker无论是由海拔intra-lysosomal引起的pH值,通过溶酶体数量增加。扩展我们先前开发的数值通过引入动态单细胞模型反馈机制。好同意的结果数值模型。数值模型导致的结果结论:intra-lysosomal积累亲脂性的外源性物质提高溶酶体膜透性。膜透性可能是有用的例如,克服耐多药改变亚细胞的药物分布。

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