Chemical Research in Toxicology最新文献

英文中文

Mechanistic Insights into CYP2A6 Inactivation by Visnagin and Its Impact on Pharmacokinetic Properties of Tegafur Visnagin使CYP2A6失活的机制及其对替加富药动学性质的影响。

IF 3.8 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* and Jiang Zheng*,

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.

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。

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引用次数: 0

Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment 毒物动力学新方法在化学品风险评估中的应用。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Chemical Research in Toxicology

Pub Date : 2025-07-22 DOI: 10.1021/acs.chemrestox.5c00161

John F. Wambaugh*, Katie Paul Friedman, Marc A. Beal, Ivy Moffat, Michael F. Hughes, Andy Nong, Jean-Lou C. M. Dorne, Muhammad Waqar Ashraf, Tara S. Barton-Maclaren, Michael DeVito, Stephen S. Ferguson, Richard S. Judson, Alexandra S. Long, Alicia Paini, Stavroula Sampani, Russell S. Thomas and Barbara A. Wetmore,

Toxicokinetic (TK) modeling provides critical information linking chemical exposures to tissue concentrations, predicting persistence in the body and determining the route(s) of elimination. Unfortunately, TK data are not available for most chemicals in commerce and the environment. To better understand and address these important information gaps, researchers and regulatory scientists from the international consortium of Accelerating the Pace of Chemical Risk Assessment herein present a flexible framework for characterizing the suitability of TK new approach methods (NAMs) to address chemical risk questions. High throughput toxicokinetics (HTTK) combines chemical-specific in vitro measures of TK with reproducible transparent and open-source TK models. HTTK supports the interpretation of data from in vitro bioactivity NAMs in a public health risk context and enhances the interpretation of biomonitoring data. A tiered framework has been developed focusing on two key aspects: (1) the regulatory decision context and (2) chemical properties and data. Differing levels of certainty are needed for relative risk prioritization, prospective risk assessment, and for protecting susceptible populations. Here HTTK is described with respect to measurement and modeling applications, relevant decision contexts, applicable chemistry, value of information, and certainty of predictions. In some cases, quantitative structure–property relationship (QSPR) models exist as alternatives to measurement and are discussed when they are appropriate. A series of examples applying the decision trees in specific public health scenarios are provided to illustrate that writing short responses, prompted by the decision trees and supported by the discussion and references collected here, may provide defensible written justification for or against the use of HTTK. The framework is intended to serve as a guide to chemical regulators and risk assessors who are interested to know when and where HTTK might be used for public health safety or risk decision making and when further expert guidance is needed.

毒物动力学（TK）模型提供了将化学物质暴露与组织浓度联系起来的关键信息，预测了体内的持久性，并确定了消除途径。不幸的是，商业和环境中的大多数化学品都没有传统知识数据。为了更好地理解和解决这些重要的信息缺口，加速化学品风险评估国际联盟的研究人员和监管科学家在此提出了一个灵活的框架，用于表征TK新方法（NAMs）解决化学品风险问题的适用性。高通量毒物动力学（HTTK）将TK的化学特异性体外测量与可重复的透明和开源TK模型相结合。HTTK支持在公共卫生风险背景下解释体外生物活性NAMs数据，并加强对生物监测数据的解释。已经开发了一个分层框架，重点关注两个关键方面：(1)监管决策背景和(2)化学性质和数据。相对风险优先排序、前瞻性风险评估和保护易感人群需要不同程度的确定性。在这里，HTTK描述了测量和建模应用、相关决策上下文、适用化学、信息价值和预测的确定性。在某些情况下，定量结构-属性关系（QSPR）模型作为测量的替代方案存在，并在适当的时候进行讨论。本文提供了一系列在特定公共卫生情景中应用决策树的例子，以说明在决策树的推动下，在本文收集的讨论和参考文献的支持下，撰写简短的答复，可以为支持或反对使用HTTK提供可辩护的书面理由。该框架旨在作为化学品监管机构和风险评估人员的指南，他们有兴趣知道何时何地可以将HTTK用于公共卫生安全或风险决策，以及何时需要进一步的专家指导。

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引用次数: 0