Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2.
Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2.
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DOI：
10.1016/j.jep.2015.07.011
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发表时间：
2015-08
影响因子：
5.4
通讯作者：
Liping Ma;Yahong Qin;Zhuowei Shen;H. Bi;Haiyong Hu;Min Huang;Hui Zhou;Lushan Yu;Huidi Jiang;S. Zeng
中科院分区：
文献类型：
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作者：
Liping Ma;Yahong Qin;Zhuowei Shen;H. Bi;Haiyong Hu;Min Huang;Hui Zhou;Lushan Yu;Huidi Jiang;S. Zeng
马兜铃酸肾病是马兜铃酸引起的一种严重的肾脏疾病，马兜铃酸广泛存在于马兜铃科植物中。马兜铃酸I（Aristolochic acid I，AAI）是马兜铃酸中的主要毒性成分。本研究探讨了AAI与肠道主要外排转运蛋白的相互作用。材料与方法首先，研究了AAI在Caco-2细胞单层中的双向转运。结果AAI在Caco-2细胞单层的外排率为5.8，提示AAI的外排转运蛋白可能参与了AAI的转运。AAI不抑制Rho 123外排的P-gp和钙黄绿素外排的MRP 2，和细胞内积累的AAI在P-gp或MRP 2过表达的细胞是没有不同的，从他们的父母细胞。这些结果表明，AAI不是P-gp或MRP 2的底物。相反，LLC-PK 1-BCRP细胞中AAI的细胞内蓄积显著低于其亲本细胞。BCRP抑制剂GF 120918的存在显著增加了BCRP过表达细胞中AAI的积累，但在其亲本细胞中没有。此外，LLC-PK 1-BCRP单层细胞中AAI的双向转运试验显示，20、40和80 µM AAI时AAI的净外排率分别为13.8、8.0和7.0，加入10 µM GF 120918后分别降至3.0、1.9和2.0。结论这些结果表明，AAI是BCRP的底物，而不是P-gp或MRP 2。
Ethnopharmacological relevanceAristolochic acid nephropathy is a severe kidney disease caused by the administration of aristolochic acid, which is widely existed in plants of the Aristolochiaceae family. Aristolochic acid I (AAI) is the main toxic component in aristolochic acid.Aim of the studyThe roles of intestinal efflux drug transporters in the transport of AAI are unclear. This study investigates the interaction between AAI and main intestinal efflux transporters.Materials and MethodsFirstly, bidirectional transport of AAI in Caco-2 cell monolayers was investigated. Then, MDCK-MDR1 (gene of P-glycoprotein (P-gp)), MDCK-MRP2 and LLC-PK1-BCRP cell lines were used for further investigation.ResultsIn this study, we observed that the efflux ratio of AAI in Caco-2 cell monolayers was 5.8, which indicated that efflux transporters might be involved in the transport of AAI. AAI did not inhibit Rho123 efflux by P-gp and calcein efflux by MRP2, and intracellular accumulation of AAI in P-gp or MRP2 overexpressing cells was not different from their parental cells. These results indicated that AAI was not a substrate of P-gp or MRP2. In contrast, intracellular accumulation of AAI in LLC-PK1-BCRP cells was significantly lower than in their parental cells. The presence of GF120918, a BCRP inhibitor, significantly increased AAI accumulation in BCRP overexpressing cells but not in their parental cells. In addition, bidirectional transport assay of AAI in LLC-PK1-BCRP monolayers showed that the net efflux ratios of AAI were 13.8, 8.0 and 7.0 at 20, 40 and 80 µM AAI, respectively, and decreased to 3.0, 1.9 and 2.0 by the addition of 10 µM GF120918.ConclusionsThese results indicated that AAI was a substrate of BCRP but not P-gp or MRP2.