Chemical Research in Toxicology最新文献_第5页

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

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*,

{"title":"Mechanistic Insights into CYP2A6 Inactivation by Visnagin and Its Impact on Pharmacokinetic Properties of Tegafur","authors":"Dandan Yang, Qing Zhang, Tingmin Ye, Zihao Cheng, Hong Tang, Jie Dai, Xueqian Cheng, Ying Peng*, Weiwei Li* and Jiang Zheng*, ","doi":"10.1021/acs.chemrestox.5c00131","DOIUrl":"10.1021/acs.chemrestox.5c00131","url":null,"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 Cmax and area under the curve of tegafur in rats.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1357–1366"},"PeriodicalIF":3.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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,

{"title":"Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment","authors":"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, ","doi":"10.1021/acs.chemrestox.5c00161","DOIUrl":"10.1021/acs.chemrestox.5c00161","url":null,"abstract":"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.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 8","pages":"1408–1441"},"PeriodicalIF":3.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-07-21

Anthony L. Su, Cátia F. Marques, Jacek Krzeminski, Karam El-Bayoumy and Trevor M. Penning*,