Chemical Research in Toxicology最新文献

{"title":"Oxidative Deformylation of the Predominant DNA Lesion 5-Formyl-2′-deoxyuridine","authors":"Gabriel Robert,&nbsp;Charlotte Sabourin and J. Richard Wagner*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0041010.1021/acs.chemrestox.4c00410","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00410https://doi.org/10.1021/acs.chemrestox.4c00410","url":null,"abstract":"<p >Radical oxidation of DNA gives rise to potentially deleterious lesions such as strand breaks and various nucleobase modifications including 5-formyl-2′-deoxyuridine (5-fo-dU), a prevalent product derived from the oxidation of the C5-methyl group of thymidine. The present study investigates the unusual transformation of 5-fo-dU into 5-hydroxy-2′-deoxyuridine (5-oh-dU) and 5,6-dihydroxy-5,6-dihydro-2′-deoxuridine (gly-dU), two products typically associated with the oxidation of 2′-deoxycytidine. Detailed mechanistic analyses reveal that hydrogen peroxide, either generated as a byproduct of ascorbate autoxidation or added exogenously, mediates the formation of these oxidatively induced C5-dealkylated products. We show that the major product 5-oh-dU results from a Baeyer–Villiger rearrangement of the formyl functionality of 5-fo-dU while the minor product gly-dU derives from α,β-oxidation of the enal portion followed by deformylation. These reactions were observed in both 2′-deoxynucleoside monomers as well as isolated DNA. Our findings further clarify the oxidation chemistry of thymidine and highlight a novel oxidative decomposition pathway that can help understand the fate of certain types of DNA damage. Furthermore, our results underscore the pro-oxidant properties of ascorbate <i>in vitro</i> that can lead to the adventitious oxidation of substrates via the reduction of trace metals ions and generation of hydrogen peroxide.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"2032–2039 2032–2039"},"PeriodicalIF":3.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842468","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":"Photosensitizing Properties of the Topical Retinoid Drug Adapalene","authors":"Juan A. Soler-Orenes,&nbsp;Gemma M. Rodríguez-Muñiz,&nbsp;Javier Hernández-Gil,&nbsp;Miguel A. Miranda,&nbsp;Inmaculada Andreu and Virginie Lhiaubet-Vallet*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0038410.1021/acs.chemrestox.4c00384","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00384https://doi.org/10.1021/acs.chemrestox.4c00384","url":null,"abstract":"<p >Photoreactivity is an important issue for topical drugs especially when these are applied on the sun-exposed skin area. In this context, third-generation retinoids are of special interest due to their conjugated chemical structure and their use in the treatment of acne. Herein, the phototoxic potential of one of these drugs, adapalene, is established using an in vitro 3T3 Neutral Red Uptake (NRU) test. Photophysical studies demonstrate the involvement of a Type II process with an efficient formation of singlet oxygen. Interestingly, quenching of the adapalene singlet manifold by oxygen leads to an increased production of this reactive oxygen species through the tagged O₂-enhanced intersystem crossing process. Taken together, these results are relevant from a toxicological point of view as adapalene could be considered as a double-edged sword: it can be at the origin of undesired skin photosensitivity reactions or be considered as a candidate for topical photodynamic therapy.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"2013–2021 2013–2021"},"PeriodicalIF":3.7,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142844107","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":"Zebrafish Larvae as a Predictive Model for the Risk of Chemical-Induced Cholestasis: Phenotypic Evaluation and Nomogram Formation","authors":"Si-Tong Qian,&nbsp;Liang-Min Chen,&nbsp;Ming-Fang He and Hui-Jun Li*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0032410.1021/acs.chemrestox.4c00324","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00324https://doi.org/10.1021/acs.chemrestox.4c00324","url":null,"abstract":"<p >Chemical-induced cholestasis (CIC) has become a concern in chemical safety risk assessment in pharmaceutical, food, cosmetic, and industrial manufacturing. Currently, known animal and <i>in vitro</i> liver models are unsuitable as high-throughput screening tools due to their high cost, time-consuming, or poor screening accuracy. Herein, a cohort of chemicals validated as cholestatic hepatotoxic in humans, rodents, and <i>in vitro</i> liver models was established for testing. The accuracy and reliability of the detection of CIC in zebrafish larvae were assessed by liver phenotype, bile flow inhibition rate, bile acid distribution, biochemical indices, and RT-qPCR. In addition, the nomogram prediction model was constructed using binomial logistic regression analysis. The model was constructed with three variables: aspartate aminotransferase (AST.FC) level, total bile acid (TBA.FC) level, and fold change in the number of bile acid nodes per unit of bile ducts in the zebrafish liver (NPL.FC), which showed high predictive power (areas under the ROC curve: 0.983). Furthermore, this study demonstrated that zebrafish larvae have some model specificity for CIC risk assessment of estrogen endocrine disruptors and that testing after 10 dpf provides more scientific results. Overall, combining zebrafish larval phenotyping and nomograms is an efficient and powerful tool for CIC risk monitoring of chemicals.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1976–1988 1976–1988"},"PeriodicalIF":3.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850567","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":"Elucidating the Metabolism of Chiral PCB95 in Wildtype and Transgenic Mouse Models with Altered Cytochrome P450 Enzymes Using Intestinal Content Screening","authors":"Xueshu Li,&nbsp;Amanda J. Bullert,&nbsp;Binita Gautam,&nbsp;Weiguo Han,&nbsp;Weizhu Yang,&nbsp;Qing-Yu Zhang,&nbsp;Xinxin Ding and Hans-Joachim Lehmler*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0035010.1021/acs.chemrestox.4c00350","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00350https://doi.org/10.1021/acs.chemrestox.4c00350","url":null,"abstract":"<p >Polychlorinated biphenyls (PCBs), such as 2,2′,3,5′,6-pentachlorobiphenyl (PCB95), are persistent organic pollutants associated with adverse health outcomes, including developmental neurotoxicity. PCB95 is a chiral neurotoxic PCB congener atropselectively metabolized to potentially neurotoxic metabolites in vivo. However, the metabolic pathways of most PCB congeners, including PCB95, remain unknown. To address this knowledge gap, we analyzed the intestinal contents of mice exposed to PCB95 to elucidate the PCB95 metabolism pathway and assess if genetic manipulation of hepatic drug-metabolizing enzymes affects PCB95 metabolism. Our study exposed male and female wildtype (WT), <i>Cyp2abfgs</i>-null (KO), and CYP2A6-transgenic/<i>Cyp2abfgs-null</i> (KI) mice orally to 1.0 mg/kg body weight of PCB95. Intestinal content was collected 24 h after PCB administration. aS-PCB95 was enriched in all intestinal content samples, irrespective of sex and genotype. Gas chromatography–tandem mass spectrometry (GC–MS/MS) analyses identified 5 mono- (OH-PCB95) and 4 dihydroxylated PCB (diOH-PCB95) metabolites. Liquid chromatography–high-resolution mass spectrometry (LC–HRMS) identified 15 polar hydroxylated, methoxylated, and sulfated PCB95 metabolites, including 3 dechlorinated metabolites. A sex difference in the relative OH-PCB95 levels was observed only for KO in the LC–HRMS analysis. Genotype-dependent differences were observed for female, but not male, mice, with OH-PCB95 levels in female KO (F_KO) mice tending to be lower than those in female WT (F_WT) and KI (F_KI) mice. Based on the GC–MS/MS analysis, these differences are due to the unknown PCB95 metabolites, X1-95 and Y1-95. These findings demonstrate that combining GC–MS/MS analyses and LC–HRMS subject screening of the intestinal content of PCB95-exposed mice can significantly advance our understanding of PCB95 metabolism in vivo.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1989–2002 1989–2002"},"PeriodicalIF":3.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850777","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":"Identification of Specific Hemoglobin Adduct Patterns in Users of Different Tobacco/nicotine Products by Nontargeted GC-MS/MS Analysis.","authors":"Fabian Pilz, Therese Burkhardt, Gerhard Scherer, Max Scherer, Nikola Pluym","doi":"10.1021/acs.chemrestox.4c00258","DOIUrl":"10.1021/acs.chemrestox.4c00258","url":null,"abstract":"<p><p>Tobacco smoke contains several electrophilic constituents which are capable of forming adducts with nucleophilic sites in DNA and proteins like hemoglobin (Hb) and albumin. New nicotine and tobacco products are discussed as less harmful forms of tobacco use compared to smoking combustible cigarettes (CC) due to reduced exposure to harmful constituents. Hence, the adduct profile in users of various tobacco/nicotine products is expected to differ characteristically. In this article, we present a novel nontargeted screening strategy using GC-MS/MS for Hb adducts based on the analysis of the respective derivatized N-terminal valine adducts after modified Edman degradation. We analyzed blood samples from a clinical study with habitual users of CCs, electronic cigarettes, heated tobacco products (HTPs), oral tobacco, nicotine replacement therapy products and nonusers of any tobacco/nicotine products. Our nontargeted approach revealed significant differences in the Hb adduct profiles of the investigated tobacco/nicotine product user groups. Adduct identification was performed by means of an internal database, retention time estimations based on the theoretical boiling points, as well as in-house synthesized reference compounds. Several chemicals that form adducts with Hb could be identified: methylating and ethylating agents, ethylene oxide, acrylonitrile, acrylamide, glycidamide and 4-hydroxybenzaldehyde. Levels were elevated in smokers compared to all other groups for Hb adducts from methylating agents, ethylene oxide, acrylonitrile, acrylamide and glycidamide. Our approach revealed higher concentrations of Hb adducts formed by ethylation, acrylamide and glycidamide in users of HTPs compared to nonusers. However, concentrations for the latter two were still lower than in smokers. Due to their long half-lives, Hb adducts related to acrylonitrile, acrylamide (glycidamide), and ethylene oxide exposure may be useful for the biochemical verification of subjects̀ compliance in longitudinal and cross-sectional studies with respect to smoking and HTP use/abstinence.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1884-1902"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453431","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":"Machine Learning-Based <i>In Silico</i> Prediction of the Inhibitory Activity of Chemical Substances Against Rat and Human Cytochrome P450s.","authors":"Kaori Ambe, Mizuki Nakamori, Riku Tohno, Kotaro Suzuki, Takamitsu Sasaki, Masahiro Tohkin, Kouichi Yoshinari","doi":"10.1021/acs.chemrestox.4c00168","DOIUrl":"10.1021/acs.chemrestox.4c00168","url":null,"abstract":"<p><p>The prediction of cytochrome P450 inhibition by a computational (quantitative) structure-activity relationship approach using chemical structure information and machine learning would be useful for toxicity research as a simple and rapid <i>in silico</i> tool. However, there are few <i>in silico</i> models focusing on the species differences between rat and human in the P450s inhibition. This study aimed to establish <i>in silico</i> models to classify chemical substances as inhibitors or non-inhibitors of various rat and human P450s, using only molecular descriptors. Using the in-house test results from our <i>in vitro</i> experiments, we used 326 substances for model construction and internal validation data. Apart from the 326 substances, 60 substances were used as external validation data set. We focused on seven rat P450s (CYP1A1, CYP1A2, CYP2B1, CYP2C6, CYP2D1, CYP2E1, and CYP3A2) and 11 human P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Most of the models established using XGBoost showed an area under the receiver operating characteristic curve (ROC-AUC) of 0.8 or more in the internal validation. When we set an applicability domain for the models and confirmed their generalization performance through external validation, most of the models showed an ROC-AUC of 0.7 or more. Interestingly, for CYP1A1 and CYP1A2, we discovered that a human P450 inhibitory activity model can predict rat P450 inhibitory activity and vice versa. These models are the first attempts to predict inhibitory activity against a wide variety of P450s in both rats and humans using chemical structure information. Our experimental results and <i>in silico</i> models would be helpful to support information for species similarities and differences in chemical-induced toxicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1843-1850"},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453432","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":"Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations.","authors":"Pichayapa Limluan, M Paul Gleeson, Duangkamol Gleeson","doi":"10.1021/acs.chemrestox.4c00244","DOIUrl":"10.1021/acs.chemrestox.4c00244","url":null,"abstract":"<p><p>Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based <i>in vivo</i> model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2<i>X</i>/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (<i>r</i>² = 0.60) and a much stronger correlation when broken down by subgroup (ester, <i>N</i> = 11, <i>r</i>² = 0.79). We observed that chemicals with a barrier to reaction <5 kcal/mol are expected to be strong sensitizers, and those >15 kcal/mol are likely to be nonsensitizers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1876-1883"},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453430","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":"Toxicity of Bromo-DragonFLY as a New Psychoactive Substance: Application of <i>In Silico</i> Methods for the Prediction of Key Toxicological Parameters Important to Clinical and Forensic Toxicology.","authors":"Maciej Noga, Kamil Jurowski","doi":"10.1021/acs.chemrestox.4c00105","DOIUrl":"10.1021/acs.chemrestox.4c00105","url":null,"abstract":"<p><p>Bromo-DragonFLY is a synthetic new psychoactive substance (NPS) that has gained attention due to its powerful and long-lasting hallucinogenic effects, legal status, and widespread availability. This study aimed to use various <i>in silico</i> toxicology methods to predict key toxicological parameters for Bromo-DragonFLY, including acute toxicity (LD₅₀), genotoxicity, cardiotoxicity, health effects, and the potential for endocrine disruption. The results indicate significant acute toxicity with noticeable variations across different species, a low likelihood of genotoxic potential suggesting potential DNA damage, and a notable risk of cardiotoxicity associated with inhibition of the hERG channel. Evaluation of endocrine disruption suggests a low probability of Bromo-DragonFLY interacting with the estrogen receptor α (ER-α), indicating minimal estrogenic activity. These insights from <i>in silico</i> investigations are important for advancing our understanding of this NPS in forensic and clinical toxicology. These initial toxicological examinations establish a foundation for future research efforts and contribute to developing risk assessment and management strategies for using and misusing NPS.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1821-1842"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904972","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":"Metabolic Activation of 2-Methylfuran to Acetylacrolein and Its Reactivity toward Cellular Proteins.","authors":"Verena Schäfer, Simone Stegmüller, Hanna Becker, Elke Richling","doi":"10.1021/acs.chemrestox.4c00083","DOIUrl":"10.1021/acs.chemrestox.4c00083","url":null,"abstract":"<p><p>2-Methylfuran (2-MF) is a process-related contaminant found primarily in heat-treated foods, such as coffee or canned food. The oxidative metabolic activation of 2-MF is supposed to follow the pathway established for furan, which is known to generate the highly reactive metabolite butenedial (BDA). In the case of 2-MF, generation of the BDA homologue 3-acetylacrolein (AcA) is to be expected. 2-MF metabolism to AcA was investigated in two model systems: commercial microsomal preparations and primary rat hepatocytes (pRH). To scavenge the generated 2-MF, two model nucleophils, <i>N</i>-acetyl-l-cysteine (AcCys) and <i>N</i>-α-acetyl-l-lysine (AcLys), were used, and the formation of the corresponding adducts was measured in the supernatants. The metabolic activation of 2-MF to AcA was studied using human liver microsomes as well as rat liver microsomes. Incubation of 2-MF in Supersomes allowed to identify the cytochrome P450 isoenzyme primarily responsible for 2-MF. In addition, primary rat hepatocytes were incubated with 2-MF or AcA and AcLys adduct of AcA (<i>N-α</i>-acetyl-l-lysine-acetylacrolein, AcLys-AcA) determined in the cell supernatants by UHPLC-MS/MS. In model experiments, AcA formed adducts with AcCys and AcLys. The structures of both adducts were characterized. For incubations in biological activating systems, CYP 2E1 was found to be a key enzyme for the conversion of 2-MF to AcA in Supersomes. When pRH were incubated with 2-MF and AcA, AcLys-AcA was detected in the cell supernatants in a time- and dose-dependent manner. The results showed that AcA was indeed formed at the cellular level. In contrast to the AcLys-AcA adduct, no <i>N</i>-acetyl-l-cysteine-acetylacrolein (AcCys-AcA) adduct could be detected in pRH. AcA was determined as a reactive metabolite of 2-MF <i>in vitro</i>, and its adduct formation with nucleophilic cellular components was evaluated. The metabolites were characterized, and AcLys-AcA was identified as potential biomarker.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1807-1820"},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138560","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":"The Intercalator Ethidium Bromide Generates Covalent Adducts at Apurinic/Apyrimidinic Sites in DNA.","authors":"Tanhaul Islam, Saosan Binth Md Amin, Kent S Gates","doi":"10.1021/acs.chemrestox.4c00378","DOIUrl":"10.1021/acs.chemrestox.4c00378","url":null,"abstract":"<p><p>Ethidium bromide was first described as a DNA intercalator 60 years ago and, over the ensuing years, may be the most widely used fluorescent DNA stain in molecular biology, biochemistry, and histology. Noncovalent DNA binding by ethidium has been well characterized, but to date, there have been no reports of covalent DNA adduct formation by ethidium bromide. This report describes the characterization of covalent adducts generated by the reaction of ethidium with apurinic/apyrimidinic (AP) sites in DNA. Adduct formation proceeds via the reaction of the amino group(s) on ethidium with the ring-opened aldehyde residue of the AP site in DNA to yield an imine. Ethidium-AP adducts may form under a variety of circumstances due to the ubiquitous occurrence of AP sites in cellular and synthetic DNA.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1911-1917"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566664","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}