Sulfonation Disposition of Acacetin: In Vitro and in Vivo
Sulfonation Disposition of Acacetin: In Vitro and in Vivo
复制标题
金合欢素的磺化处理：体外和体内
DOI：
10.1021/acs.jafc.7b00854
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发表时间：
2017
影响因子：
6.1
通讯作者：
Liu Zhongqiu
中科院分区：
文献类型：
--
作者：
Zhang Qisong;Zhu Lijun;Gong Xia;Ruan Yanjiao;Yu Jia;Jiang Huangyu;Wang Ying;Qi XiaoXiao;Lu Linlin;Liu Zhongqiu
金合欢素是金合欢蜂蜜的重要成分，对多种癌症有广泛的治疗作用。然而，刺槐素的磺化处置很少有报道。因此，本研究旨在系统地研究刺槐素的磺化反应。结果表明，金合欢素-7-硫酸酯是主要的代谢产物，主要由磺基转移酶（SULT）1A 1介导。犬肝S9中金合欢素-7-硫酸盐的形成率最高。与野生型Friend病毒B（FVB）小鼠相比，多药耐药蛋白1基因敲除（Mrp 1-/-）小鼠的金合欢素-7-硫酸酯血浆暴露量显著降低，而乳腺癌耐药蛋白基因敲除（Bcrp-/-）小鼠的金合欢素-7-硫酸酯血浆暴露量显著升高。在Caco-2单层细胞中，顶侧的BCRP抑制剂Ko 143和基底侧的MRP 1抑制剂MK 571明显降低了金合欢素-7-硫酸盐的外排和清除。总之，金合欢素磺化主要由SULT 1A 1介导。发现金合欢素-7-硫酸盐主要通过BCRP和MRP 1转运。因此，SULT 1A 1、BCRP和MRP 1负责体内金合欢素-7-硫酸盐暴露。
Acacetin, an important component of acacia honey, exerts extensive therapeutic effects on many cancers. However, the sulfonation disposition of acacetin has rarely been reported. Therefore, this study aimed to investigate the sulfonation disposition of acacetin systematically. The results showed that acacetin-7-sulfate was the main metabolite mediated primarily by sulfotransferases (SULT) 1A1. Dog liver S9 presented the highest formation rate of acacetin-7-sulfate. Compared with that in wild-type Friend Virus B (FVB) mice, plasma exposure of acacetin-7-sulfate decreased significantly in multidrug resistance protein 1 knockout (Mrp1–/–) mice vut increased clearly in breast cancer resistance protein knockout (Bcrp–/–) mice. In Caco-2 monolayers, the efflux and clearance of acacetin-7-sulfate was reduced distinctly by the BCRP inhibitor Ko143 on the apical side and by the MRP1 inhibitor MK571 on the basolateral side. In conclusion, acacetin sulfonation was mediated mostly by SULT1A1. Acacetin-7-sulfate was found to be transported mainly by BCRP and MRP1. Hence, SULT1A1, BCRP, and MRP1 are responsible for acacetin-7-sulfate exposure in vivo.