维生素E对去甲丙咪嗪及其他阳离子两亲性药物在人培养细胞中诱导的药物蓄积和磷脂沉积症的抑制作用。

Inhibition by vitamin E of drug accumulation and of phospholipidosis induced by desipramine and other cationic amphiphilic drugs in human cultured cells.

作者信息

Scuntaro I, Kientsch U, Wiesmann U N, Honegger U E

机构信息

Department of Pharmacology, University of Bern, Switzerland.

出版信息

Br J Pharmacol. 1996 Nov;119(5):829-34. doi: 10.1111/j.1476-5381.1996.tb15747.x.

DOI:10.1111/j.1476-5381.1996.tb15747.x

PMID:8922728

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1915950/

Abstract

Cationic amphiphilic drugs (CADs) are widely used in chronic pharmacotherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2. It has recently been shown that alpha-tocopherol (alpha-Toc) inhibits drug- and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3. The mechanisms of alpha-Toc action on drug kinetics and PL storage were studied in human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. 4. alpha-Toc did not influence the initial, pH-dependent rapid phase of drug uptake. It inhibited, in a dose-dependent manner, the slow and the cumulative phases of drug uptake and coincidently the accumulation of cellular PLs. 5. The inhibitory effects of alpha-Toc on CAD and PL accumulations depends on the ratio between CAD and alpha-Toc concentrations in the medium. This points to competition between alpha-Toc and CADs for PL complex formation. 6. Effectiveness of alpha-Toc on drug uptake varies among different CADs. It depends on its structural integrity but is independent of stereoisomerism. The inhibitory action is restricted to the piggyback slow drug uptake and therefore related to the proportion of membrane-mediated transport to permeation into lysosomes (rapid uptake). This proportion differs among CADs. 7. alpha-Toc prevents lysosomal membrane-PL storage, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that alpha-Toc restores membrane recycling, impaired by CAD exposure. 8. It remains to be tested in vivo whether alpha-Toc reduces CAD side effects without interfering with drug effectiveness.

摘要

阳离子两亲性药物（CADs）尽管经常出现与溶酶体磷脂（PL）储存相关的副作用，但仍广泛用于慢性药物治疗。2. 最近有研究表明，α-生育酚（α-Toc）可抑制长期暴露于CAD胺碘酮的细胞培养物中药物和PL的积累。3. 在暴露于单剂量和重复剂量地昔帕明及其他CADs的人培养成纤维细胞中，研究了α-Toc对药物动力学和PL储存的作用机制。4. α-Toc不影响药物摄取的初始pH依赖性快速阶段。它以剂量依赖性方式抑制药物摄取的缓慢和累积阶段，并同时抑制细胞PL的积累。5. α-Toc对CAD和PL积累的抑制作用取决于培养基中CAD与α-Toc浓度的比例。这表明α-Toc与CADs在形成PL复合物方面存在竞争。6. α-Toc对不同CADs药物摄取的有效性各不相同。它取决于其结构完整性，但与立体异构无关。抑制作用仅限于搭便车式的缓慢药物摄取，因此与膜介导运输与渗透到溶酶体（快速摄取）的比例有关。不同CADs的这一比例有所不同。7. α-Toc可防止溶酶体膜PL储存，加速PL储存的分解，并使与药物相关的膜流动性增加恢复正常。这强烈表明α-Toc可恢复因CAD暴露而受损的膜再循环。8. α-Toc是否能在不干扰药物疗效的情况下减少CAD的副作用，仍有待于在体内进行测试。