蒽醌类化合物大黄酚和大黄素甲醚对人类细胞色素CYP1B1的抑制作用
Inhibition of human cytochrome CYP1B1 by anthraquinone compounds,chrysophanol and physcion
贾力维 1周蕾 1王振月 1王谦博 2刘笑妍 3孟鑫1
作者信息
- 1. 黑龙江中医药大学药学院,哈尔滨 150040
- 2. 广东药科大学附属第一医院药剂科,广州 510062
- 3. 中国药科大学药学院,南京 211198
- 折叠
摘要
使用乙氧基试卤灵作为底物,评估了大黄酚和大黄素甲醚对CYP1B1的抑制作用.这些化合物对CYP1B1的抑制动力学通过逐步增加乙氧基试卤灵的剂量进行评估.抑制动力学结果显示,大黄酚(IC50(0.47±0.01)μmol·L-1)和大黄素甲醚(IC50(0.35±0.02)μmol·L-1)对 CYP1B1的催化能力均具有明显的抑制作用.大黄酚的Vmax和Km 值分别为(51.991 2±10.054 7)pmol·μg-1(protein)·min-1 和(0.966 3±0.298 7)nmol·L-1,而大黄素甲醚的 Vmax和 Km 值分别为(45.422 7±1.997 8)pmol·μg-1(protein)·min-1 和(0.436 7±0.038 6)nmol·L-1.动力学分析表明,大黄酚和大黄素甲醚均具有混合性抑制作用.这种混合抑制主要表现为化合物能够竞争性地结合CYP1B1的活性位点,同时也可能通过非竞争性机制降低酶的催化效率.通过分子对接研究蒽醌衍生物与CYP1B1之间的相互作用,分子对接结果表明,蒽醌衍生物可能通过附着在酶的活性位点上抑制CYP1B1.大黄酚和大黄素甲醚阻止CYP1B1的催化功能的能力揭示了它们的抗癌机制之一,有助于了解蒽醌衍生物结构和其CYP1B1抑制能力之间的联系,为开发新的癌症治疗药物做出探索.
Abstract
The in vitro inhibitory effects of chrysophanol and physcion on CYP1B1 were explored,utilizing ethoxyresorufin as the substrate.The inhibition kinetics of CYP1B1 by these compounds were assessed with escalating doses of ethoxyresorufin.Both chrysophanol(IC50(0.47±0.01)μmol·L-1)and physcion(IC50(0.35±0.02)μmol·L-1)significantly reduce the catalytic efficiency of CYP1B1.The Vmax and Km values are determined to be(51.991 2±10.054 7)pmol·μg-1(protein)·min-1 and(0.966 3±0.298 7)nmol·L-1 for chrysophanol,and(45.422 7±1.997 8)pmol·μg-1(protein)·min-1 and(0.4367±0.038 6)nmol·L-1 for physcion,respectively.Kinetic analysis reveals that chrysophanol and physcion exert mixed inhibitory effects on CYP1B1.This mixed inhibition is primarily characterized by the compounds'ability to competitively bind to the active sites of CYP1B1,as well as potentially through non-competitive mechanisms,thereby reducing the enzyme's catalytic efficiency.Molecular docking studies are conducted to elucidate the interaction between anthraquinone derivatives and CYP1B1,indicating that these compounds may inhibit CYP1B1 activity by binding to their active sites.The demonstrated capacity of chrysophanol and physcion to inhibit CYP1B1 enzymatic function unveils a potential anticancer mechanism,advancing our comprehension of how the structure of anthraquinone derivatives correlates with CYP1B1 inhibition and paving the way for developing innovative cancer treatments.
关键词
CYP1B1/大黄酚/大黄素甲醚/蒽醌衍生物/酶抑制剂Key words
CYP1B1/chrysophanol/physcion/anthraquinone derivative/enzyme inhibitor引用本文复制引用
基金项目
Heilongjiang Administration of Traditional Chinese Medicine(ZHY2020-078)
Education Department of Heilongjiang Province(SJGY20210830)
出版年
2024
NETL
NSTL
万方数据