Aristolochic acid I is a substrate of BCRP but not P-glycoprotein or MRP2

作者 Ma, Liping; Qin, Yahong; Shen, Zhuowei; Bi, Huichang; Hu, Haiyong; Huang, Min; Zhou, Hui; Yu, Lushan; Jiang, Huidi; Zeng, Su

期刊 JOURNAL OF ETHNOPHARMACOLOGY , AUG 22 2015,:172

DOI 10.1016/j.jep.2015.07.011 PubMed 26183576

摘要 Ethnopharmacological relevance: Aristolochic 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 study: The 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 Methods: Firstly, 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.Results: In 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 AN 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 mu M AAI, respectively, and decreased to 3.0, 1.9 and 2.0 by the addition of 10 mu M GF120918.Conclusions: These results indicated that AAI was a substrate of BCRP but not P-gp or MRP2. (C) 2015 Published by Elsevier Ireland Ltd.