HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter
HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter
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DOI：
10.1021/bi972709x
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发表时间：
1998-03-17
期刊：
影响因子：
2.9
通讯作者：
Dey, S
中科院分区：
文献类型：
--
作者：
Lee, CGL;Gottesman, MM;Dey, S
FDA批准的HIV-1蛋白酶抑制剂利托那韦、沙奎那韦和茚地那韦在抑制HIV-1复制方面非常有效，但其长期疗效尚不清楚。由于体内疗效取决于这些药物进入HIV-1复制的细胞内位点，我们确定这些蛋白酶抑制剂是否被MDR 1多药转运蛋白（P-糖蛋白或P-gp）识别，从而减少其细胞内积累。在表达MDR 1的重组杆状病毒感染的昆虫细胞分离膜制备物中进行的体外研究表明，这些抑制剂显著刺激P-gp特异性ATP酶活性，并且这种刺激可被SDZ PSC 833（一种强效P-gp抑制剂）抑制。此外，P-gp与底物类似物[I-125]碘芳基叠氮吡唑嗪（IAAP）的光亲和标记被所有三种抑制剂抑制。基于细胞的方法评价这些蛋白酶抑制剂竞争转运已知P-gp底物的能力，结果表明，所有三种HIV-1蛋白酶抑制剂均能够抑制某些已知P-gp底物的转运，但其作用通常弱于其他已记录的P-gp调节剂，如维拉帕米或环孢菌素A。所有三种蛋白酶抑制剂对HIV-1复制的抑制作用均降低，但在表达MDR 1的细胞中可通过MDR 1抑制剂恢复。这些结果表明，HIV-1蛋白酶抑制剂是人多药转运蛋白的底物，表明表达MDR 1转运蛋白的患者细胞对HIV-1蛋白酶抑制剂的抗病毒作用具有相对抗性，并且这些抑制剂在体内的吸收、排泄和分布可能受到多药转运蛋白的影响。
The FDA approved HIV-1 protease inhibitors, ritonavir, saquinavir, and indinavir, are very effective in inhibiting HIV-1 replication, but their long-term efficacy is unknown. Since in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether these protease inhibitors are recognized by the MDR1 multidrug transporter (P-glycoprotein, or P-gp), thereby reducing their intracellular accumulation. In vitro studies in isolated membrane preparations from insect cells infected with MDR1-expressing recombinant baculovirus showed that these inhibitors significantly stimulated P-gp-specific ATPase activity and that this stimulation was inhibited by SDZ PSC 833, a potent inhibitor of P-gp. Furthermore, photoaffinity labeling of P-gp with the substrate analogue [I-125]iodoarylazidoprazosin (IAAP) was inhibited by all three inhibitors. Cell-based approaches to evaluate the ability of these protease inhibitors to compete for transport of known P-gp substrates showed that all three HIV-1 protease inhibitors were capable of inhibiting the transport of some of the known P-gp substrates but their effects were generally weaker than other documented P-gp modulators such as verapamil or cyclosporin A. Inhibition of HIV-1 replication by all three protease inhibitors was reduced but could be restored by MDR1 inhibitors in cells expressing MDR1. These results indicate that the HIV-1 protease inhibitors are substrates of the human multidrug transporter, suggesting that cells in patients that express the MDR1 transporter will be relatively resistant to the anti-viral effects of the HIV-1 protease inhibitors, and that absorption, excretion, and distribution of these inhibitors in the body may be affected by the multidrug transporter.