Su Junhui, Chang Cui, Xiang Qi, Zhou Zhi-Wei, Luo Rong, Yang Lun, He Zhi-Xu, Yang Hongtu, Li Jianan, Bei Yu, Xu Jinmei, Zhang Minjing, Zhang Qihao, Su Zhijian, Huang Yadong, Pang Jiyan, Zhou Shu-Feng
Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, People's Republic of China ; Department of Pharmacy, Jinan University, Guangzhou, People's Republic of China ; The People's Hospital of Shenzhen City, Shenzhen, People's Republic of China.
The People's Hospital of Shenzhen City, Shenzhen, People's Republic of China.
Drug Des Devel Ther. 2014 Dec 12;8:2555-602. doi: 10.2147/DDDT.S73476. eCollection 2014.
Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug-drug interactions via the chemical-protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1'-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1'-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members.
天然化合物在疾病治疗和健康促进方面正变得越来越受欢迎，但其作用机制和安全性概况往往尚不明确。木酮糖酮B（XKB）是一种从红树林真菌木层孔菌属中分离出的新型海洋化合物，具有强大的抗氧化、神经保护和心脏保护作用。然而，其分子靶点以及对药物代谢酶的影响尚不清楚。本研究旨在使用生物信息学方法研究XKB的潜在分子靶点，并以咪达唑仑作为模型探针，研究XKB对大鼠细胞色素P450 3a（Cyp3a）亚家族成员的表达和活性的影响。利用可通过化学-蛋白质相互作用组预测药物-药物相互作用的服务器DDI-CPI来预测XKB的靶点，并使用注释、可视化和综合发现数据库（DAVID）分析XKB预测靶点的通路。使用Discovery Studio程序3.1进行同源建模。大鼠连续8天接受7和14 mg/kg的XKB治疗后，检测大鼠肝脏Cyp3a的活性和表达。使用经过验证的高效液相色谱法测定大鼠血浆中咪达唑仑及其代谢物1'-羟基-咪达唑仑的浓度。生物信息学分析表明，有超过324种功能蛋白和61条相关信号通路可能受XKB调控。分子对接研究表明，XKB通过形成氢键与人细胞色素P450 3A4的活性位点和大鼠Cyp3a2同源模型结合。体内研究表明，给大鼠口服14 mg/kg的XKB，持续8天，可显著增加咪达唑仑的血浆浓度-时间曲线下面积（AUC），同时降低血浆清除率以及1'-羟基-咪达唑仑与咪达唑仑的AUC比值。此外，口服14 mg/kg的XKB，持续8天，可显著降低大鼠肝脏Cyp3a的活性和表达。综上所述，结果表明XKB可调节分子蛋白网络和相关信号通路，且XKB可下调大鼠肝脏中的Cyp3a。XKB可能通过调节Cyp3a成员的活性和表达引起药物相互作用。需要更多研究来证实XKB的作用机制，并研究XKB对Cyp3a亚家族成员调节作用的潜在机制。
