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Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity
Xenobiotica ( IF 1.8 ) Pub Date : 2021-08-09 , DOI: 10.1080/00498254.2021.1961920
Dongxue Sun 1, 2 , Xiaoxia Gao 2, 3 , Qiao Wang 4 , Kristopher W Krausz 2 , Zhongze Fang 2, 5 , Youbo Zhang 2, 6 , Cen Xie 2, 7 , Frank J Gonzalez 2
Affiliation  

Abstract

  1. Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo.

  2. Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.

  3. A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.

  4. Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.

  5. POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.

  6. This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.



中文翻译:

抗病毒药物鬼臼毒素的代谢图提供了对肝毒性的见解

摘要

  1. 鬼臼毒素(POD)是一种具有抗病毒和抗癌活性的天然化合物。本研究的目的是确定 POD在体外体内的代谢图。

  2. 小鼠和人肝微粒体用于体外鉴定 POD 代谢物,重组药物代谢酶用于鉴定参与 POD 代谢的单加氧酶。用超高效液相色谱结合电喷雾电离四极杆飞行时间质谱分析来自用 POD 处理的小鼠的所有体外培养混合物和胆汁样品。

  3. 从口服给药后的胆汁和粪便样品中鉴定出POD的38种代谢物,包括6种I期代谢物和32种II期代谢物,并通过解释MS/MS碎片模式阐明了它们的结构。

  4. 在人和小鼠肝微粒体孵育系统中检测到九种代谢物,包括两种 I 期代谢物、五种葡糖苷酸结合物和两种 GSH 结合物,并且所有代谢物的产生都是 NADPH 依赖性的。参与 POD体外代谢的主要 I 期酶包括 CYP2C9、CYP2C19、CYP3A4 和 CYP3A5。

  5. POD 对小鼠给药会引起肝脏和肠道毒性,当 1-氨基苯并三唑(一种 CYP 的广谱抑制剂)与 POD 一起给药时,细胞损伤会加剧,这表明 POD(而不是其代谢物)会引起肝脏和肠道毒性。

  6. 本研究阐明了代谢图谱,为POD的安全性评价和临床应用的合理性提供了重要的参考依据。

更新日期:2021-09-01
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