Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes
Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes
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血根碱对人肝细胞色素P450酶的抑制作用
DOI：
10.1016/j.fct.2013.02.054
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发表时间：
2013-06-01
影响因子：
4.3
通讯作者：
Tu, Cai-Xia
中科院分区：
文献类型：
--
作者：
Qi, Xiao-Yi;Liang, Si-Cheng;Tu, Cai-Xia
血根碱(SAG)已被公认为抗癌候选药物。然而，SAG通过抑制人细胞色素P450(CYP)酶的药物-药物相互作用(DDI)潜力仍不清楚。用人肝微粒体(HLM)研究了SAG对人CYP 7种主要亚型1A2、2A6、2E1、2D6、2C8、2C9和3A4的抑制作用。结果表明，SAG对细胞色素P450 2C8活性具有较强的非竞争性抑制作用(K-I=8.9mU M)，对细胞色素P1A2、细胞色素P3A9和细胞色素P3A4有竞争性抑制作用(K-I分别为2.7、3.8和2.0mU M)。此外，SAG对细胞色素P1A2和3A4的抑制作用具有时间和NADPH依赖性，其K-I/k分别为13.3/0.087和5.58/0.029 m in(-1)mU~(-1)。SAG对细胞色素P450-2E_1、D_6和A_6的抑制作用也较弱。体外-活体外推(IV-IVE)显示，体内超过35.9%的细胞色素P1A2、细胞色素P450亚型C9、细胞色素P450 C8和细胞色素P3A4活性可被SAG抑制，提示当SAG或其药物制剂与这些CYP亚型主要清除的药物联合给药时，可能会发生有害的DDIS。还需要进一步的体内研究来评估本文所提供的数据的临床意义。(C)2013爱思唯尔有限公司。保留所有权利。
Sanguinarine (SAG) has been recognized as an anticancer drug candidate. However, the drug-drug interactions (DDI) potential for SAG via the inhibition against human cytochrome P450 (CYP) enzymes remains unclear. In the present study, the inhibitory effects of SAG on seven major human CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C8, 2C9 and 3A4 were investigated with human liver microsomes (HLM). The results showed that SAG was a potent noncompetitive inhibitor of CYP2C8 activity (K-i = 8.9 mu M) and competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4 activities (K-i = 2.7, 3.8 and 2.0 mu M, respectively). Furthermore, SAG exhibited time- and NADPH-dependent inhibition towards CYP1A2 and CYP3A4 with K-i/k(inact) values of 13.3/0.087 and 5.58/0.029 min(-1) mu M-1, respectively. Weak inhibition of SAG against CYP2E1, CYP2D6 and CYP2A6 was also observed. In vitro-in vivo extrapolation (IV-IVE) from HLM data showed that more than 35.9% of CYP1A2, CYP2C9, CYP2C8 and CYP3A4 activities in vivo could be inhibited by SAG, suggesting that harmful DDIs could occur when SAG or its medical preparations are co-administered with drugs primarily cleared by these CYP isoforms. Further in vivo studies are needed to evaluate the clinical significance of the data presented herein. (C) 2013 Elsevier Ltd. All rights reserved.