Shen Zhijie, Wang Yingjie, Guo Wei, Yao Yili, Wang Xiaolong
Cardiovascular Department, Shuguang Hospital Affiliated to Shanghai University of TCM Shanghai, China.
Am J Transl Res. 2016 Dec 15;8(12):5545-5556. eCollection 2016.
Many researches have proved functions of anti-oxidation, endothelial protection and pro-angiogenesis efficiency of Shexiang Baoxin Pill (SBP). This study aims to investigate potential for metabolism-based interaction on CYP450s and transporter based interaction on OATP1B1, BRCP and MDR1. Human primary hepatocytes were used in this study. Probe substrates of cytochrome P450 enzymes were incubated in human liver microsomes (HLMs) with or without SBP and IC values were estimated. Inhibitive potential of SBP on activities of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 was evaluated. Inducible potential of SBP on activities of CYP1A2, 2B6 and 3A4 was accessed. Inhibitive potential of SBP on human OATP1B1 was evaluated using cell-based assay. Inhibitive potential of SBP on human MDR1 and BCRP was also evaluated using vesicles assay. MDR1 and BCRP vesicle kit were used to determine ATP dependent uptake activity when incubated with SBP. SBP was a competitive inhibitor of CYP2B6, 2C19, while neither inhibitory nor inductive potentials toward other CYP450s were detected. No significant MDR1 inhibitory potential was estimated, while only high concentration of SBP (500 μg/ml) could inhibit activity of BCRP. Probe substrates Estradiol-17 β-glucuronide was incubated in HEK293-OATP1B1 and HEK293-MOCK cell system with different concentration of SBP and estimated IC was 179 μg/mL, which demonstrated a moderate inhibition potential against OATP1B1. In conclusion, outcome of this study suggests that SBP plays an important role in inhibition of CYP450 isozymes (including CYP2B6 and 2C9) and transporter OATP1B1. Therefore, precautions should be taken when using SBP for CYP and OATP-related herb-drug interactions.
多项研究已证实麝香保心丸（SBP）具有抗氧化、内皮保护及促血管生成功效。本研究旨在探讨SBP基于代谢的对细胞色素P450（CYP450s）的相互作用潜力以及基于转运体的对有机阴离子转运多肽1B1（OATP1B1）、乳腺癌耐药蛋白（BRCP）和多药耐药蛋白1（MDR1）的相互作用潜力。本研究采用人原代肝细胞。细胞色素P450酶的探针底物在有或无SBP的人肝微粒体（HLMs）中孵育，并估算半数抑制浓度（IC）值。评估SBP对CYP1A2、2B6、2C8、2C9、2C19、2D6和3A4活性的抑制潜力。评估SBP对CYP1A2、2B6和3A4活性的诱导潜力。使用基于细胞的试验评估SBP对人OATP1B1的抑制潜力。还使用囊泡试验评估SBP对人MDR1和BRCP的抑制潜力。当与SBP孵育时，使用MDR1和BRCP囊泡试剂盒测定ATP依赖性摄取活性。SBP是CYP2B6、2C19的竞争性抑制剂，而未检测到对其他CYP450s的抑制或诱导潜力。未估算出显著的MDR1抑制潜力，而只有高浓度的SBP（500μg/ml）可抑制BRCP活性。探针底物17β-葡萄糖醛酸雌二醇在不同浓度SBP的人胚肾293细胞（HEK293）-OATP1B1和HEK293-空载体细胞系统中孵育，估算出的IC为179μg/mL，表明对OATP1B1有中度抑制潜力。总之，本研究结果表明SBP在抑制CYP450同工酶（包括CYP2B6和2C9）和转运体OATP1B1中起重要作用。因此，在使用SBP时应注意其与CYP和OATP相关的药-药相互作用。
