黄酮 - 8 - 乙酸在小鼠体内的代谢

Metabolism of Flavone-8-acetic Acid in Mice.

作者信息

Pham Minh Hien, Auzeil Nicolas, Regazzetti Anne, Scherman Daniel, Seguin Johanne, Mignet Nathalie, Dauzonne Daniel, Chabot Guy G

机构信息

Chemical, Genetic and Imaging Pharmacology Laboratory, Faculty of Pharmacy, Chimie ParisTech, Paris Descartes University, Sorbonne Paris Cité, INSERM U1022, CNRS UMR8151, Paris, France Medical Oncology and Cellular Therapy Department, Tenon Hospital, Public Assistance Hospitals of Paris, Alliance for Cancer Research, Paris, France Laboratory of Therapeutic Drug Monitoring, Platform for Peptidomic, Metabolomic and Drug Measurements, Saint Antoine Hospital, Paris, France

Platform of Mass spectrometry, Faculty of Pharmacy (IFR 71), University Paris Descartes, Paris, France.

出版信息

Anticancer Res. 2016 Aug;36(8):3889-98.

PMID:27466491

Abstract

Flavone-8-acetic acid (FAA) is a potent antivascular agent in mice but not in humans. Assuming that FAA was bioactivated in mice, we previously demonstrated that 6-OH-FAA was formed from FAA by mouse microsomes but not by human microsomes; its antivascular activity was 2.1- to 15.9-fold stronger than that of FAA, and its antivascular activity was mediated through the Ras homolog gene family (Rho) protein kinase A (RhoA) pathway. The present work aimed to study FAA metabolism in order to verify if 6-OH-FAA is formed in mice. Using synthesized standards and high-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) detection and mass spectrometry (MS) analysis, we herein demonstrated, for the first time, that in vitro FAA and its monohydroxylated derivatives could directly undergo phase II metabolism forming glucuronides, and two FAA epoxides were mostly scavenged by NAC and GSH forming corresponding adducts. FAA was metabolized in mice. Several metabolites were formed, in particular 6-OHFAA. The antitumor activity of 6-OH-FAA in vivo is worthy of investigation.

摘要

黄酮 - 8 - 乙酸（FAA）在小鼠中是一种有效的抗血管生成剂，但在人类中并非如此。假设FAA在小鼠体内被生物活化，我们之前证明6 - 羟基 - FAA（6 - OH - FAA）是由小鼠微粒体而非人类微粒体从FAA形成的；其抗血管生成活性比FAA强2.1至15.9倍，并且其抗血管生成活性是通过Ras同源基因家族（Rho）蛋白激酶A（RhoA）途径介导的。目前的工作旨在研究FAA的代谢，以验证6 - OH - FAA是否在小鼠体内形成。使用合成标准品以及高效液相色谱（HPLC）结合紫外（UV）检测和质谱（MS）分析，我们在此首次证明，体外FAA及其单羟基化衍生物可直接进行Ⅱ相代谢形成葡糖醛酸苷，并且两种FAA环氧化物大多被N - 乙酰半胱氨酸（NAC）和谷胱甘肽（GSH）清除形成相应的加合物。FAA在小鼠体内发生代谢。形成了几种代谢产物，特别是6 - OH - FAA。6 - OH - FAA在体内的抗肿瘤活性值得研究。