Chemical Research in Toxicology最新文献

{"title":"Peptide Sequence and Cross-Link Structure Influence Translesion Synthesis Polymerase Bypass of 5-Formylcytosine-Mediated DNA-Peptide Cross-Links.","authors":"Qi Zhang, Iwen Fu, Suse Broyde, Natalia Y Tretyakova","doi":"10.1021/acs.chemrestox.5c00215","DOIUrl":"10.1021/acs.chemrestox.5c00215","url":null,"abstract":"<p><p>DNA-peptide cross-links (DpCs) are generated via the proteolytic cleavage of DNA-protein cross-links (DPCs), ubiquitous DNA lesions that block DNA replication and transcription. Translesion synthesis (TLS) DNA polymerases can facilitate replication bypass of DpC adducts in either an error-free or error-prone manner. We have previously demonstrated that local DNA sequence context significantly influences hPol <i>η</i>-mediated replication bypass of 5-formylcytosine (5fC)-mediated DpC lesions. However, the effects of peptide sequence on the efficiency and fidelity of the TLS bypass of 5fC-mediated DpC lesions remained unknown. In the present study, model DpCs containing three different peptides (NH₂-GGGKGLG<b>K*</b>GGA-COOH, NH₂-RP<b>K*</b>PQQFFGLM-COOH, and NH₂-RPKPQQF<b>K*</b>GLM-COOH, <b>K*</b> = oxy-lysine) were subjected to primer extension experiments in the presence of TLS polymerases. We found that <i>in vitro</i> replication of DpC-containing templates by hPol <i>η</i> was more efficient than that catalyzed by hPol <i>l</i> or hPol κ. HPLC-ESI-MS and HPLC-ESI-MS/MS analyses of hPol <i>η</i> primer extension products indicated that the replication bypass of DpC containing NH₂-RP<b>K</b>*PQQFFGLM-COOH was more error-prone than replication of the other two DpCs, leading to targeted C → T transitions, small deletions, and untargeted mutations downstream from the lesion. Steady-state kinetics investigation of hPol <i>η</i>-catalyzed nucleotide incorporation opposite the DpC lesions containing three different peptides revealed that, in all cases, error-free replication was far more efficient than incorporation of incorrect nucleotides. For mutagenic bypass, the catalytic efficiency of hPol <i>η</i>-mediated dAMP misincorporation opposite DpC with peptide NH₂-RP<b>K*</b>PQQFFGLM-COOH was higher than adenine misincorporation across from the other two DpCs and unmodified dC. These steady-state kinetic findings were further explained by molecular modeling and molecular dynamics simulations, revealing that the three different DpC lesions impose varying perturbations to the geometry of the C-G and C-A pairs at the hPol <i>η</i> active site. Collectively, our results reveal that the peptide sequence and conjugation chemistry of DpC lesions can influence the fidelity of lesion bypass by TLS polymerases.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725975","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}

{"title":"Aetokthonotoxin, the Causative Agent of Vacuolar Myelinopathy, Uncouples Oxidative Phosphorylation due to Protonophore Activity","authors":"Valerie I. C. Rebhahn,&nbsp;Mohamad Saoud,&nbsp;Mathias Winterhalter,&nbsp;Franziska Schanbacher,&nbsp;Maximilian Jobst,&nbsp;Rebeca Ruiz,&nbsp;Alexander Sonntag,&nbsp;Johannes Kollatz,&nbsp;Rieke Sprengel,&nbsp;Stephen F. Donovan,&nbsp;Giorgia Del Favero,&nbsp;Robert Rennert and Timo H. J. Niedermeyer*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00147","DOIUrl":"10.1021/acs.chemrestox.5c00147","url":null,"abstract":"<p >Aetokthonotoxin (AETX) is an emerging environmental toxin produced by the freshwater cyanobacterium <i>Aetokthonos hydrillicola</i>. Accumulating in the food chain, it causes vacuolar myelinopathy, a neurological disease affecting a wide range of wildlife characterized by the development of large intramyelinic vacuoles in the white matter of the brain. So far, the mode of action of AETX is unknown. After discovering that AETX is cytostatic and arrests cancer cell lines in the G₁ phase, metabolomic profiling of AETX-treated cells as well as an assessment of the physicochemical properties of the compound suggested that AETX is a weakly acidic uncoupler of mitochondrial respiration. We confirmed this hypothesis by <i>in vitro</i> assays on mammalian cells, finding that AETX has the expected effects on mitochondrial network morphology, mitochondrial membrane potential, and oxygen consumption rate, resulting in affected ATP generation. We confirmed that AETX is capable of transporting protons across lipid bilayers. In summary, we demonstrate that AETX is a protonophore that uncouples oxidative phosphorylation in mitochondria, which is the primary event of AETX intoxication.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 9","pages":"1495–1508"},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights into CYP2A6 Inactivation by Visnagin and Its Impact on Pharmacokinetic Properties of Tegafur","authors":"Dandan Yang,&nbsp;Qing Zhang,&nbsp;Tingmin Ye,&nbsp;Zihao Cheng,&nbsp;Hong Tang,&nbsp;Jie Dai,&nbsp;Xueqian Cheng,&nbsp;Ying Peng*,&nbsp;Weiwei Li* and Jiang Zheng*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00131","DOIUrl":"10.1021/acs.chemrestox.5c00131","url":null,"abstract":"<p >Visnagin (VNG), a furanochromone, is a major active component of the plant <i>Ammi visnaga</i> (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 <i>C</i>_max and area under the curve of tegafur in rats.</p>","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}

{"title":"Applying New Approach Methods for Toxicokinetics for Chemical Risk Assessment","authors":"John F. Wambaugh*,&nbsp;Katie Paul Friedman,&nbsp;Marc A. Beal,&nbsp;Ivy Moffat,&nbsp;Michael F. Hughes,&nbsp;Andy Nong,&nbsp;Jean-Lou C. M. Dorne,&nbsp;Muhammad Waqar Ashraf,&nbsp;Tara S. Barton-Maclaren,&nbsp;Michael DeVito,&nbsp;Stephen S. Ferguson,&nbsp;Richard S. Judson,&nbsp;Alexandra S. Long,&nbsp;Alicia Paini,&nbsp;Stavroula Sampani,&nbsp;Russell S. Thomas and Barbara A. Wetmore,&nbsp;","doi":"10.1021/acs.chemrestox.5c00161","DOIUrl":"10.1021/acs.chemrestox.5c00161","url":null,"abstract":"<p >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.</p>","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}

{"title":"","authors":"Anthony L. Su,&nbsp;Cátia F. Marques,&nbsp;Jacek Krzeminski,&nbsp;Karam El-Bayoumy and Trevor M. Penning*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Hiroshi Yamazaki*,&nbsp; and ,&nbsp;Makiko Shimizu,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Puthiyavalappil Rasin*,&nbsp; and ,&nbsp;Praveena Prabhakaran,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Shufang Qi,&nbsp;Li Cai,&nbsp;Xinmiao Lu,&nbsp;Shaowei Wang,&nbsp;Siming Shao,&nbsp;Nikita Jacintha Hector,&nbsp;Baiping Mao,&nbsp;Yiyan Wang*,&nbsp;Ren-Shan Ge* and Wangning Shangguan*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Emily M. Kaye,&nbsp;Jitka Becanova,&nbsp;Simon Vojta,&nbsp;Rainer Lohmann,&nbsp;Fabian Christoph Fischer* and Angela Slitt*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.4c00508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"38 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/txv038i007_1961693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}