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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2)
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HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2)

机译：HIV蛋白酶抑制剂是人乳腺癌抗性蛋白（BCRP / ABCG2）的抑制剂，但不是底物

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摘要

Breast cancer resistance protein (BCRP) is a recently discovered ATP-binding cassette drug transporter.Hence,the full spectrum of therapeutic agents that interact with BCRP remains to be elucidated.Because human immunodeficiency virus protease inhibitors (HPIs) are well known P-glycoprotein (P-gp) substrates,and there is an overlap in substrate specificity between P-gp and BCRP,this study was performed to investigate whether HPIs are substrates and/or inhibitors of BCRP.First,the effect of HPIs on BCRP efflux activity in human embryonic kidney (HEK) cells stably expressing wild-type BCRP (482R) and its two mutants (482T and 482G) was studied by measuring intracellular mitoxantrone fluorescence using flow cytometry.We found that ritonavir,saquinavir,and nelfi-navir were effective inhibitors of wild-type BCRP (482R) with IC_(50) values of 19.5+-0.8muM,19.5+-7.6muM,and 12.5+-4.1 muM,respectively.Ritonavir,saquinavir,and nelfinavir inhibited 482T and 482G with IC_(50) values that were approximately 2 times greater than that for 482R.Indinavir and amprenavir had no significant inhibition on BCRP activity.Direct efflux of radio-labeled HPIs in HEK cells was measured to determine whether the HPIs are substrates of BCRP.None of the HPIs were found to be transported by BCRP.Together,ritonavir,saquinavir,nelfinavir,indinavir,and amprenavir are not substrates for BCRP.However,ritonavir,saquinavir,and nelfinavir are effective inhibitors of the transporter.These results suggest that BCRP may play an important role in drug-drug interactions involving coadministration of the HPIs with drugs that are substrates of the transporter.
机译：乳腺癌抗性蛋白（BCRP）是最近发现的与ATP结合的盒式药物转运蛋白。因此，与BCRP相互作用的治疗剂的全范围仍有待阐明。由于人类免疫缺陷病毒蛋白酶抑制剂（HPI）是众所周知的P-糖蛋白（P-gp）底物，并且P-gp和BCRP之间存在底物特异性重叠，本研究旨在研究HPI是否是BCRP的底物和/或抑制剂。首先，HPI对动物体内BCRP外排活性的影响。通过流式细胞仪检测细胞内的米托蒽醌荧光，研究了稳定表达野生型BCRP（482R）及其两个突变体（482T和482G）的人胚胎肾（HEK）细胞。我们发现利托那韦，沙奎那韦和纳非那韦是有效的抑制剂IC_（50）值分别为19.5 +-0.8μM，19.5 +-7.6μM和12.5 + -4.1μM的野生型BCRP（482R）.Ritonavir，saquinavir和nelfinavir抑制IC_（50）的482T和482G ）的价值比482R高2倍，茚地那韦和氨普那韦对BCRP活性没有明显的抑制作用，测量放射性标记的HPI在HEK细胞中的直接流出，以确定HPI是否是BCRP的底物，没有发现HPI是ritonavir，saquinavir，nelfinavir，indinavir和amprenavir并非BCRP的底物。但是，ritonavir，saquinavir和nelfinavir是转运蛋白的有效抑制剂。这些结果表明BCRP可能在药物-药物相互作用涉及HPI与作为转运蛋白底物的药物的共同给药。

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