Mechanistic Insights into CYP2A6 Inactivation by Visnagin and Its Impact on Pharmacokinetic Properties of Tegafur.

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Chemical Research in Toxicology Pub Date : 2025-07-22 DOI:10.1021/acs.chemrestox.5c00131

Dandan Yang, Qing Zhang, Tingmin Ye, Zihao Cheng, Hong Tang, Jie Dai, Xueqian Cheng, Ying Peng, Weiwei Li, Jiang Zheng

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Abstract

Visnagin (VNG), a furanochromone, is a major active component of the plant Ammi visnaga (L.) Lam often used for the preparation of tea products. This study aims to comprehensively investigate the mechanism of VNG-mediated CYP2A6 enzyme inactivation and the effects of VNG on the pharmacokinetics of the antitumor drug tegafur. The results demonstrate that VNG irreversibly inhibits CYP2A6 in a time-, concentration-, and NADPH-dependent manner. This time-dependent inhibition was attenuated by coincubation with letrozole, a competitive inhibitor of CYP2A6. Glutathione and hydrogen peroxide/superoxide dismutase failed to reverse the VNG-induced inactivation of CYP2A6. GSH trapping experiments provided strong evidence for the formation of epoxide and/or γ-ketoaldehyde intermediates resulting from the metabolic activation of VNG. Furthermore, pretreatment with VNG extract significantly increased the plasma C_max and area under the curve of tegafur in rats.

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Visnagin使CYP2A6失活的机制及其对替加富药动学性质的影响。

Visnagin （VNG）是一种呋喃酮，是植物Ammi visnaga （L.）的主要活性成分。蓝常用于制备茶制品。本研究旨在全面探讨VNG介导的CYP2A6酶失活机制及VNG对抗肿瘤药物替加富的药代动力学影响。结果表明，VNG以时间、浓度和nadph依赖的方式不可逆地抑制CYP2A6。与来曲唑（一种CYP2A6竞争性抑制剂）共孵育后，这种时间依赖性抑制减弱。谷胱甘肽和过氧化氢/超氧化物歧化酶未能逆转vng诱导的CYP2A6失活。GSH捕获实验提供了强有力的证据，证明了VNG代谢激活导致环氧化物和/或γ-酮醛中间体的形成。此外，VNG提取物预处理可显著提高大鼠血浆Cmax和替加氟曲线下面积。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Research in Toxicology 医学-毒理学

CiteScore

7.90

自引率

7.30%

发文量

215

审稿时长

3.5 months

期刊介绍： Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.