Chemical Research in Toxicology最新文献_第8页

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16

Abbey Rebok, Mariela C. Torres, Julia R. Ambrose and Thomas E. Spratt*,

引用次数: 0

Catalytic-Dependent Role of DNA Polymerase κ in Nucleotide Excision Repair. DNA聚合酶κ在核苷酸切除修复中的催化依赖性作用。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-05-25 DOI: 10.1021/acs.chemrestox.5c00085

Abbey Rebok, Mariela C Torres, Julia R Ambrose, Thomas E Spratt

{"title":"Catalytic-Dependent Role of DNA Polymerase κ in Nucleotide Excision Repair.","authors":"Abbey Rebok, Mariela C Torres, Julia R Ambrose, Thomas E Spratt","doi":"10.1021/acs.chemrestox.5c00085","DOIUrl":"10.1021/acs.chemrestox.5c00085","url":null,"abstract":"DNA polymerase kappa (pol κ) is an error-prone Y-family polymerase primarily associated with translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that prevents replication fork stalling. Pol κ has been implicated in other DNA repair and tolerance pathways such as nucleotide excision repair (NER). However, the role of error-prone pol κ in the NER pathway remains unclear. We sought to investigate if pol κ had a catalytic role in NER by using the pol κ selective nucleoside analogue, N2-(4-ethynylbenzyl)-2'-deoxyguanosine (EBndG). Here, we identified robust, cell cycle-independent catalytic activity of pol κ in cells not treated with DNA-damaging agents. We identified approximately 40% of pol κ catalytic activity was reduced with loss of either XPC or XPA, but not CSB, indicating pol κ has a role in global genome-NER. We monitored pol κ catalytic activity after treatment with benzo(a)pyrene diol epoxide and UVB radiation, and we observed that pol κ catalytic activity increased in an NER-dependent manner. Our study highlights that pol κ is consistently active in cells and possesses a key catalytic role in NER.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1103-1112"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140870","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 : 2025-06-16

June K. Dunnick*, Charles P. Schmitt and Darlene Dixon*,

引用次数: 0

Facile Biological Oxidation of Dopamine to 6-Hydroxydopamine p-Quinone in a Sequential Two-Step Process: Implications for Parkinson's Disease. 在连续的两步过程中，多巴胺易氧化为6-羟基多巴胺对醌：对帕金森病的影响

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-06-04 DOI: 10.1021/acs.chemrestox.5c00058

Xiang-Rong Jiang, Bao Ting Zhu

{"title":"Facile Biological Oxidation of Dopamine to 6-Hydroxydopamine p-Quinone in a Sequential Two-Step Process: Implications for Parkinson's Disease.","authors":"Xiang-Rong Jiang, Bao Ting Zhu","doi":"10.1021/acs.chemrestox.5c00058","DOIUrl":"10.1021/acs.chemrestox.5c00058","url":null,"abstract":"6-Hydroxydopamine (6-OHDA), a hydroxyl-derivative of the endogenous neurotransmitter dopamine, can selectively induce Parkinsonian symptoms in animal models. At present, most researchers consider 6-OHDA a man-made neurotoxicant, due to the lack of strong evidence for its presence and/or formation in biological systems. The present study aims to determine whether 6-OHDA can be formed under physiologically relevant conditions. Here, we report in the Fenton reaction system (containing 15 μM Fe2+, 142 μM ascorbic acid and 80 μM EDTA in 50 mM phosphate buffer, pH 7.4), dopamine can undergo facile oxidation to 6-OHDA p-quinone (a stable, oxidized form of 6-OHDA) in a sequential two-step process: the first step involves dopamine oxidation to its o-quinone (DAQ), and this process is facilitated by oxidants like transition metal ions Fe2+/3+ and Mn2+/3+; and the second step involves the further oxidization of DAQ to 6-OHDA p-quinone by hydroxyl radical or hydrogen peroxide. The chemical mechanism by which H2O2 oxidizes DAQ to 6-OHDA p-quinone likely results from the attack of H2O2-derived -OOH at the C-6 position of DAQ. We also demonstrate that while catalase abolishes 6-OHDA p-quinone formation by removing hydrogen peroxide or hydroxyl radical, glutathione and cysteine provide effective protection by forming conjugates with DAQ and 6-OHDA p-quinone. The results of this study demonstrate that 6-OHDA can be readily formed from dopamine under physiologically relevant conditions, and thus provide important tangible support for the long-held speculation that 6-OHDA is an intrinsic etiological factor in Parkinson's disease.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1082-1090"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223711","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

Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism. 全氟和多氟烷基物质抑制巨噬细胞替代激活，破坏肝脏脂质代谢。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-05-29 DOI: 10.1021/acs.chemrestox.5c00066

Lijuan You, Xiaohong Wang, Yuan Zhi, Huiling Wang, Zhisen Zhuang, Jing Yang, Qiannan Zhang, Hailin Shang, Yongning Li, Yi Wan, Xudong Jia, Hui Yang

{"title":"Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism.","authors":"Lijuan You, Xiaohong Wang, Yuan Zhi, Huiling Wang, Zhisen Zhuang, Jing Yang, Qiannan Zhang, Hailin Shang, Yongning Li, Yi Wan, Xudong Jia, Hui Yang","doi":"10.1021/acs.chemrestox.5c00066","DOIUrl":"10.1021/acs.chemrestox.5c00066","url":null,"abstract":"Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects (e.g., hepatotoxicity and metabolism disorder). Macrophages played a key role in metabolic response; however, the effect of macrophage on PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we constructed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into alternative activation of macrophages, enabling rapid quantitative screening of numerous PFAS. We applied the cell model to screen 10 PFASs and identified that PFOA and PFUnDA significantly suppressed alternative activation of macrophages by disrupting the PPAR signaling pathway. Oral exposure to PFOA and PFUnDA in WT mice also significantly impaired alternative activation of macrophages in the liver and induced hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Moreover, macrophage-specific knockout of PPARγ exacerbated PFOA and PFUnDA-induced suppression of macrophage alternative activation and subsequent hepatotoxicity. Activation balance between PPARα and PPARγ may be a critical factor by PFOA and PFUnDA to affect the alternative activation of macrophage. These findings highlight the immunometabolism regulatory role of macrophage activation in PFAS-induced hepatotoxicity in humans.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1091-1102"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172199","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

Evaluation of the Effectiveness of l-Ergothioneine in Conjunction with Reactive Intermediates Derived from Model Pharmaceuticals. l-麦角硫因与模型药物衍生的反应性中间体联合使用的有效性评估。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-06-02 DOI: 10.1021/acs.chemrestox.5c00112

Jianyao Wang, Lu Chen, Kaushik Mitra

{"title":"Evaluation of the Effectiveness of l-Ergothioneine in Conjunction with Reactive Intermediates Derived from Model Pharmaceuticals.","authors":"Jianyao Wang, Lu Chen, Kaushik Mitra","doi":"10.1021/acs.chemrestox.5c00112","DOIUrl":"10.1021/acs.chemrestox.5c00112","url":null,"abstract":"During our investigation into a compound's disposition within our discovery portfolio, we identified an l-ergothioneine to generate reactive intermediates. These drugs included acetaminophen, diclofenac, carbamazepine, clozapine, nefazodone, raloxifene, tamoxifen, ticlopidine, troglitazone, and ethacrynic acid. The drugs were incubated with human liver microsomes supplemented with NADPH and ET, followed by analysis with liquid chromatography-mass spectrometry (LC-MS). This process led to the detection of ET conjugates in six of the ten compounds, which exhibited structural differences: for instance, acetaminophen, raloxifene, and troglitazone presented with +ET-2H, while diclofenac, nefazodone, troglitazone, and tamoxifen showed +O + ET-2H. Additionally, nefazodone yielded +ET + O-HCl. The paper discusses structure-activity relationships (SAR) and underlying mechanisms. The proposed structures indicate that ET effectively incorporates reactive intermediates featuring highly conjugated moieties, such as quinones and quinone-imines, yet is less effective with epoxides, α-β-unsaturated ketones, and nitrenium ions. To further investigate ET's detoxification capabilities, we analyzed metabolic products from acetaminophen, diclofenac, nefazodone, and raloxifene using rat, monkey, and human hepatocytes without GSH and ET supplementation. Interestingly, we detected conjugates of ET and GSH corresponding to +ET/GSH-2H and +O + ET/GSH-2H. Notably, our findings suggest that, in addition to scavenging reactive oxygen species, ET can also shield cells from reactive xenobiotic intermediates, similar to GSH. This research presents the first evidence of ET's role as a trapping agent for reactive drug intermediates.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1113-1121"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207148","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

A Comparative Assessment of the FDA List of 93 HPHCs in Aerosol Generated by Tobacco Heating System 2.2 versus 3R4F Reference Cigarette Smoke. 烟草加热系统2.2与参考香烟烟雾3R4F产生的气溶胶中93种HPHCs的FDA清单的比较评估

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-05-21 DOI: 10.1021/acs.chemrestox.4c00544

Serge Maeder, Cyril Jeannet

{"title":"A Comparative Assessment of the FDA List of 93 HPHCs in Aerosol Generated by Tobacco Heating System 2.2 versus 3R4F Reference Cigarette Smoke.","authors":"Serge Maeder, Cyril Jeannet","doi":"10.1021/acs.chemrestox.4c00544","DOIUrl":"10.1021/acs.chemrestox.4c00544","url":null,"abstract":"The US Food and Drug Administration (FDA) published an inventory of harmful and potentially harmful constituents (HPHCs), which lists 93 chemicals (FDA 93) linked to the serious health effects of tobacco use. Some of the chemical compounds in the FDA 93 list were not characterized in earlier studies due to methodological limitations at that time. Leveraging new analytical methods, the current study quantitatively assessed an expanded list of 108 HPHCs in the tobacco heating system (THS) aerosol compared with smoke from the 3R4F reference cigarette. Analyses were conducted by Labstat International ULC, an independent laboratory accredited by the Standard Council of Canada to ISO/IEC 17025:2017, on two different THS HeatStick variants (regular and menthol) together with the THS version 2.2 and the 3R4F reference cigarette smoke using a Health Canada Intense smoking regime. Of the 108 HPHCs assessed in this study, 105 were either below the limits of quantification or showed substantial reductions in THS aerosol relative to cigarette smoke (all >45%), with no increased HPHC levels in the THS aerosol relative to cigarette smoke. Aside from nicotine, anabasine, and polonium-210 (210Po) which was near the limits of detection), the average reduction in the levels of HPHCs in the aerosol of THS compared with 3R4F reference cigarette smoke was >91.6% (Regular) and >92.2% (Menthol). The results for the two THS tobacco stick variants were remarkably similar. These results confirm that the elimination of combustion in THS results in a substantial reduction of HPHCs relative to cigarette smoke.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1037-1045"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109095","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}

引用次数: 0

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16

Linyuan Huang, Ruiyang Ding, Kanglin Yan, Junchao Duan and Zhiwei Sun*,

引用次数: 0

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16

Jianyao Wang*, Lu Chen and Kaushik Mitra,

引用次数: 0

A Review of the Most Frequent Compounds, Metals, and Compound and Metal Mixtures Found at U.S. Superfund Sites and Their Carcinogenic Potential. 在美国超级基金遗址发现的最常见的化合物、金属、化合物和金属混合物及其致癌潜力的综述。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2025-06-16 Epub Date: 2025-06-03 DOI: 10.1021/acs.chemrestox.4c00506

June K Dunnick, Charles P Schmitt, Darlene Dixon

{"title":"A Review of the Most Frequent Compounds, Metals, and Compound and Metal Mixtures Found at U.S. Superfund Sites and Their Carcinogenic Potential.","authors":"June K Dunnick, Charles P Schmitt, Darlene Dixon","doi":"10.1021/acs.chemrestox.4c00506","DOIUrl":"10.1021/acs.chemrestox.4c00506","url":null,"abstract":"The United States Environmental Protection Agency's (U.S. EPA) National Priorities List (NPL) is a list of sites in the U.S. and its territories of national priority that are sources of known hazardous contaminants, pollutants, or substances that pose a significant risk to human health and the environment. These sites are commonly termed U.S. Superfund sites and contain many harmful compounds and metals. This paper reviews the carcinogenic potential of the most frequent compounds, metals, and mixtures at U.S. Superfund sites. Of the most frequent compounds and metals identified at U.S. Superfund sites, some are classified as human carcinogens and some as probable/possible human carcinogens. The most frequent mixtures of three individual carcinogenic compound or metals at U.S. Superfund sites include: nickel, arsenic, and cadmium (496 sites); benzene, arsenic, trichloroethene (451 sites); benzene, vinyl chloride, trichloroethene (420 sites); and arsenic, vinyl chloride, trichloroethene (386 sites). Many compounds or metals that are frequently found at U.S. Superfund Sites have not been evaluated for carcinogenic activity because of limited data including copper, xylene, mercury, barium, and iron. Factors in human cancer development include both environmental factors and genetic disease susceptibility backgrounds. Thus, future mixture toxicology studies should be conducted with a design that looks at mixture toxicology in a variety of models with varied genetic backgrounds.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"963-974"},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214333","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}

引用次数: 0