Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport
Inhibitory Effects of Terpenoids on Multidrug Resistance-Associated Protein 2- and Breast Cancer Resistance Protein-Mediated Transport
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DOI：
10.1124/dmd.107.019513
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发表时间：
2008-07
影响因子：
3.9
通讯作者：
Naoko Yoshida;T. Takada;Y. Yamamura;I. Adachi;H. Suzuki;J. Kawakami
中科院分区：
文献类型：
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作者：
Naoko Yoshida;T. Takada;Y. Yamamura;I. Adachi;H. Suzuki;J. Kawakami
天然产品/补充剂与常规处方药之间相互作用的可能性是药物安全性中最重要的问题之一。近年来，我们发现了一些萜类化合物如（R）-（+）-香茅醛和大黄酸等，它们具有P-糖蛋白（MDR 1/ABCB 1）抑制剂的作用。在本研究中，7萜类化合物的多药耐药相关蛋白2（MRP 2/ABCC 2）和乳腺癌耐药蛋白（BCRP/ABCG 2）介导的运输的影响进行了研究在体外。从来自草地贪夜蛾（一种秋粘虫）蛹卵巢组织的MRP 2 cDNA转染的Sf 9细胞和来自猪肾的BCRP cDNA转染的LLC-PK 1细胞制备膜囊泡。通过快速过滤技术收集的膜囊泡中[3 H]雌二醇17-β-d-葡萄糖醛酸苷（E217βG）的ATP依赖性蓄积，测定MRP 2或BCRP介导的外排转运。研究了（R）-（+）-香茅醛、（S）-（-）-β-香茅醇、α-萜品烯、萜品油烯、（-）-β-蒎烯、松香酸和甘草次酸对[3 H]E217βG囊泡内蓄积的影响。在存在甘草次酸和松香酸的情况下，观察到[3 H]E217βG蓄积到来自MRP 2过表达Sf 9细胞的囊泡中大幅减少，其IC 50值分别约为20和51 μM。[3 H]E217βG在BCRP过表达LLC-PK 1细胞囊泡中的蓄积仅受大黄酸抑制，IC 50值约为39 μM。本研究中使用的其他萜类化合物未改变[3 H]E217βG的ATP依赖性蓄积。这些结果表明，甘草次酸和松香酸可以有效地抑制MRP 2或BCRP介导的膜转运，并可能在药代动力学过程中与其底物相互作用。
The possibility of interactions between natural products/supplements and conventional prescription medicines is one of the most important issues in pharmacotherapeutic safety. Recently, we reported that some terpenoids such as (R)-(+)-citronellal and glycyrrhetic acid, which are present in herbal medicines, can act as inhibitors of P-glycoprotein (MDR1/ABCB1). In the present study, the effects of seven terpenoids on multidrug resistance-associated protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2)-mediated transport were investigated in vitro. Membrane vesicles were prepared from MRP2 cDNA transfected Sf9 cells derived from pupal ovarian tissue of Spodoptera frugiperda, a fall armyworm, and BCRP cDNA transfected LLC-PK1 cells derived from porcine kidney. MRP2- or BCRP-mediated efflux transport was measured as ATP-dependent accumulation of [3H]estradiol 17-β-d-glucuronide (E217βG) into membrane vesicles collected by a rapid filtration technique. The effects of (R)-(+)-citronellal, (S)-(-)-β-citronellol, α-terpinene, terpinolene, (-)-β-pinene, abietic acid, and glycyrrhetic acid on the intravesicular accumulation of [3H]E217βG were examined. Large decreases in the [3H]E217βG accumulation into vesicles from MRP2-overexpressing Sf9 cells were observed in the presence of glycyrrhetic acid and abietic acid, and their IC50 values were about 20 and 51 μM, respectively. [3H]E217βG accumulation into vesicles from BCRP-overexpressing LLC-PK1 cells was suppressed by only glycyrrhetic acid, with an IC50 value of about 39 μM. Other terpenoids used in this study did not alter the ATP-dependent accumulation of [3H]E217βG. These findings suggest that glycyrrhetic acid and abietic acid can potently inhibit MRP2- or BCRP-mediated membrane transport and may interact with their substrates in pharmacokinetic processes.