苯并二氮䓬类药物对 MRP1 和 P-糖蛋白活性的差异作用。

Differential effect of phenothiazines on MRP1 and P-glycoprotein activity.

机构信息

Department of Biophysics, Wrocław Medical University, Wrocław, Poland.

出版信息

In Vivo. 2009 Nov-Dec;23(6):943-7.

PMID:20023237

Abstract

BACKGROUND

Overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) or breast cancer resistance protein (BCRP) accounts for majority of cases of multidrug resistance (MDR) of cancer cells.

MATERIALS AND METHODS

In the present work, the interactions of seven commercially available phenothiazine derivatives, known P-glycoprotein inhibitors, with this transporter and MRP1 were compared. By flow cytometry, it was shown that all the drugs increased the accumulation of rhodamine 123 in the P-gp-overexpressing lymphoma cell line L5178 MDR. On the other hand, phenothiazine derivatives stimulated MRP1-mediated efflux of fluorescent probe (BCPCF) out of human erythrocytes.

RESULTS

In this way, these phenothiazine derivatives were identified as a group of atypical MDR modulators that differently interact with P-gp (as inhibitors) and MRP1 (as stimulators).

CONCLUSION

This observation clearly shows that the activity of all new modulators should be tested for their effects towards different ABC transporters as a standard procedure.

摘要

背景

ATP 结合盒（ABC）转运蛋白的过度表达，如 P 糖蛋白（P-gp）、多药耐药相关蛋白 1（MRP1）或乳腺癌耐药蛋白（BCRP），是癌细胞多药耐药（MDR）的主要原因。

材料与方法

在本工作中，比较了七种市售的吩噻嗪衍生物（已知的 P-糖蛋白抑制剂）与该转运蛋白和 MRP1 的相互作用。通过流式细胞术表明，所有药物均增加了 P-gp 过表达淋巴瘤细胞系 L5178 MDR 中罗丹明 123 的积累。另一方面，吩噻嗪衍生物刺激了人红细胞中荧光探针（BCPCF）的 MRP1 介导的外排。