Chemical Research in Toxicology最新文献_第4页

Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz. CYP2B6 的活性变化决定了依非韦伦的代谢分层。

IF 4.3 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-10-14 DOI: 10.1021/acs.chemrestox.4c00230

Xin-Yue Li, Qian Liu, Xiao-Yu Xu, Jing Wang, Yun-Shan Zhong, Le-Hao Jin, Jing Yuan, Jian-Chang Qian, Xiao-Dan Zhang

{"title":"Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz.","authors":"Xin-Yue Li, Qian Liu, Xiao-Yu Xu, Jing Wang, Yun-Shan Zhong, Le-Hao Jin, Jing Yuan, Jian-Chang Qian, Xiao-Dan Zhang","doi":"10.1021/acs.chemrestox.4c00230","DOIUrl":"10.1021/acs.chemrestox.4c00230","url":null,"abstract":"Purpose: To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the in vivo and in vitro metabolism of efavirenz.Main methods: In vitro enzyme systems using rat and human liver microsomes (RLM/HLM) were established, with in vivo studies conducted on Sprague-Dawley rats. Metabolite detection was performed via LC-MS/MS. Human recombinant CYP2B6 microsomes were prepared using a baculovirus-insect cell system and ultracentrifugation, with efavirenz serving as the substrate to study enzyme kinetics.Results: Isavuconazole exhibited an IC50 of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC50 of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, Tmax, and Cmax of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, Tmax, and Cmax of 8-OH-efavirenz. The activity of CYP2B6.4, 6, and 7 increased significantly compared to CYP2B6.1, with relative clearance ranging from 158.34% to 212.72%. Conversely, the activity of CYP2B6.3, 8, 10, 11, 13-15, 18-21, 23-27, 31-33, and 37 was markedly reduced, ranging from 4.30% to 79.89%.Conclusion: Variations in liver enzyme activity and CYP2B6 genetic polymorphisms can significantly alter the metabolism of efavirenz. It provides laboratory-based data for the precise application of efavirenz and other CYP2B6 substrate drugs.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1867-1875"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453428","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

Mitochondrial Dysfunction in Environmental Toxicology: Mechanisms, Impacts, and Health Implications. 环境毒理学中的线粒体功能障碍：环境毒理学中的线粒体功能障碍：机理、影响和健康意义》。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-11-01 DOI: 10.1021/acs.chemrestox.4c00328

Mingyang Zuo, Mingqi Ye, Haofeng Lin, Shicheng Liao, Xiumei Xing, Jianjun Liu, Desheng Wu, Zhenlie Huang, Xiaohu Ren

{"title":"Mitochondrial Dysfunction in Environmental Toxicology: Mechanisms, Impacts, and Health Implications.","authors":"Mingyang Zuo, Mingqi Ye, Haofeng Lin, Shicheng Liao, Xiumei Xing, Jianjun Liu, Desheng Wu, Zhenlie Huang, Xiaohu Ren","doi":"10.1021/acs.chemrestox.4c00328","DOIUrl":"10.1021/acs.chemrestox.4c00328","url":null,"abstract":"Mitochondria, pivotal to cellular metabolism, serve as the primary sources of biological energy and are key regulators of intracellular calcium ion storage, crucial for maintaining cellular calcium homeostasis. Dysfunction in these organelles impairs ATP synthesis, diminishing cellular functionality. Emerging evidence implicates mitochondrial dysfunction in the etiology and progression of diverse diseases. Environmental factors that induce mitochondrial dysregulation raise significant public health concerns, necessitating a nuanced comprehension and classification of mitochondrial-related hazards. This review systematically adopts a toxicological perspective to illuminate the biological functions of mitochondria, offering a comprehensive exploration of how toxicants instigate mitochondrial dysfunction. It delves into the disruption of energy metabolism, the initiation of mitochondrial fragility and autophagy, and the induction of mutations in mitochondrial DNA by mutagens. The overarching objective is to enhance our understanding of the repercussions of mitochondrial damage on human health.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1794-1806"},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556538","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

Deploying Validated Mass Spectrometry for Frontline Detection and Treatment of Human Poisoning by Long-Acting Anticoagulant Rodenticides. 将经过验证的质谱法用于长效抗凝灭鼠剂人类中毒的一线检测和治疗。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-10-29 DOI: 10.1021/acs.chemrestox.4c00344

Richard B van Breemen, Bianca Flores, Israel Rubinstein, Douglas L Feinstein

引用次数: 0

Practical Aspects of Flavin-Containing Monooxygenase-Mediated Metabolism. 含黄素单氧化酶介导的新陈代谢的实践方面。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-11-01 DOI: 10.1021/acs.chemrestox.4c00316

John R Cashman

引用次数: 0

Environmental Stability Determines the Cytotoxicity of Metal-Organic Frameworks to a Nitrogen-Fixing Bacterium Azotobacter vinelandii. 环境稳定性决定了金属有机框架对固氮菌 "醋兰氮杆菌 "的细胞毒性。

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 DOI: 10.1021/acs.chemrestox.4c00385

Ziqi Tang, Chengzhuang Liang, Qinmei Zhong, Jinwei Yang, Yusen Ma, Yue Yuan, Yiming Zeng, Xian Wu, Sheng-Tao Yang

{"title":"Environmental Stability Determines the Cytotoxicity of Metal-Organic Frameworks to a Nitrogen-Fixing Bacterium Azotobacter vinelandii.","authors":"Ziqi Tang, Chengzhuang Liang, Qinmei Zhong, Jinwei Yang, Yusen Ma, Yue Yuan, Yiming Zeng, Xian Wu, Sheng-Tao Yang","doi":"10.1021/acs.chemrestox.4c00385","DOIUrl":"10.1021/acs.chemrestox.4c00385","url":null,"abstract":"During widespread applications of metal-organic frameworks (MOFs), the environmental hazards and risks of MOFs have aroused great concerns. In this study, we aimed to reveal the importance of the environmental stability of MOFs on their toxicity. Two Zn-MOFs, namely, ZIF-8 with high aqueous stability and Zn-BDC with low aqueous stability, were compared directly in the toxicological evaluations of a nitrogen-fixing bacterium Azotobacter vinelandii. Zn-BDC showed strong cytotoxicity at 100 mg/L and higher, inducing growth inhibition, cell apoptosis, structural changes, oxidative damage, and, consequently, loss of nitrogen fixation ability. In contrast, ZIF-8 was nearly nontoxic to A. vinelandii. The transcriptome analysis showed that Zn-BDC directly disturbed the ribosome pathway and lowered the expression level of nitrogen-fixing nif cluster genes. On the other hand, ZIF-8 stress could regulate the flagellar assembly, siderophore group nonribosomal peptide biosynthesis, bacterial chemotaxis, and amino sugar and nucleotide sugar metabolism pathways to promote the cell growth of A. vinelandii. Beyond that, the toxicity of Zn-MOFs to A. vinelandii was associated with the release of Zn2+, but Zn-MOFs were less toxic than the mixtures of their starting materials. Overall, our results suggested that the environmental stability of Zn-MOFs determined their environmental toxicity through different molecular pathways. Designing stable MOFs is preferred due to environment-friendly considerations.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666418","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

Discovery and Enzyme Kinetic Characterization of Novel CYP2D6 Variants. 新型 CYP2D6 变体的发现和酶动力学特性分析

IF 4.3 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-10-21 DOI: 10.1021/acs.chemrestox.4c00298

Yun-Shan Zhong, Qi-Hui Kong, Jing Wang, Feng Ye, Xin-Yue Li, Li-Qun Zhang, Da-Peng Dai, Guo-Xin Hu, Jian-Ping Cai, Jian-Chang Qian, Fu-Sui Ji

{"title":"Discovery and Enzyme Kinetic Characterization of Novel CYP2D6 Variants.","authors":"Yun-Shan Zhong, Qi-Hui Kong, Jing Wang, Feng Ye, Xin-Yue Li, Li-Qun Zhang, Da-Peng Dai, Guo-Xin Hu, Jian-Ping Cai, Jian-Chang Qian, Fu-Sui Ji","doi":"10.1021/acs.chemrestox.4c00298","DOIUrl":"10.1021/acs.chemrestox.4c00298","url":null,"abstract":"Cytochrome P450 2D6 (CYP2D6) exhibits rich genetic polymorphism, and functional changes caused by variations are the key reasons for differences in substrate drug systemic exposure. Discovering novel variants and defining their enzymatic kinetic characteristics can contribute to the personalized application of drugs. In this study, a data chain of variant-function-structure was established through population-based sequencing, baculovirus insect cell expression, in vitro enzymatic incubation, and ultrahigh performance liquid chromatography tandem mass spectrometry. Results revealed nine novel missense mutations in the exonic regions. After the corresponding microsomes were obtained, the kinetics of the variants were investigated using dextromethorphan as a probe substrate. It was found that the activities of CYP2D6.2, 10, 17, 35, 65, R28G, T76M, and E215K were significantly reduced, while D301V almost led to loss of enzyme function. Additionally, the relative clearance rate of R25Q was significantly increased. From the molecular structure perspective, the mutation sites are distributed outside the dextromethorphan binding pocket, suggesting that they primarily influence CYP2D6 activity via allosteric modulation. These research findings provide fundamental data for the precise application of CYP2D6 substrate drugs.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1903-1910"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453429","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

Cell Painting and Chemical Structure Read-Across Can Complement Each Other for Rat Acute Oral Toxicity Prediction in Chemical Early Derisking. 细胞绘制和化学结构读数交叉可在化学品早期风险预测中对大鼠急性经口毒性进行互补。

IF 4.3 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-18 Epub Date: 2024-11-08 DOI: 10.1021/acs.chemrestox.4c00169

Fabrice Camilleri, Joanna M Wenda, Claire Pecoraro-Mercier, Jean-Paul Comet, David Rouquié

{"title":"Cell Painting and Chemical Structure Read-Across Can Complement Each Other for Rat Acute Oral Toxicity Prediction in Chemical Early Derisking.","authors":"Fabrice Camilleri, Joanna M Wenda, Claire Pecoraro-Mercier, Jean-Paul Comet, David Rouquié","doi":"10.1021/acs.chemrestox.4c00169","DOIUrl":"10.1021/acs.chemrestox.4c00169","url":null,"abstract":"Early derisking decisions in the development of new chemical compounds enable the identification of novel chemical candidates with improved safety profiles. In vivo studies are traditionally conducted in the early assessment of acute oral toxicity of crop protection products to avoid compounds, which are considered \"very acutely toxic\", with an in vivo lethal dose of 50% (LD50) ≤ 60 mg/kg body weight. Those studies are lengthy and costly and raise ethical concerns, catalyzing the use of nonanimal alternatives. The objective of our analysis was to assess the predictive efficacy of read-across approaches for acute oral toxicity in rats, comparing the use of chemical structure information, in vitro biological data derived from the Cell Painting profiling assay on U2OS cells, or the combination of both. Our findings indicate that the classification of compounds as very acute oral toxic (LD50 ≤ 60 mg/kg) or not is possible using a read-across approach, with chemical structure information, morphological profiles, or a combination of both. When classifying compounds structurally similar to those in the training set, the chemical structure was more predictive (balanced accuracy of 0.82). Conversely, when the compounds to be classified were structurally different from those in the training set, the morphological profiles were more predictive (balanced accuracy of 0.72). Combining the two models allowed for the classification of compounds structurally similar to those in the training set to slightly improve the predictions (balanced accuracy of 0.85).","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1851-1866"},"PeriodicalIF":4.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602436","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

Plant-Derived and Synthetic Nicotine in E-Cigarettes: Is Differentiation with NMR Spectroscopy Possible?

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-15 DOI: 10.1021/acs.chemrestox.4c0039810.1021/acs.chemrestox.4c00398

Yulia B. Monakhova*, Klaudia Adels and Bernd W.K. Diehl,

{"title":"Plant-Derived and Synthetic Nicotine in E-Cigarettes: Is Differentiation with NMR Spectroscopy Possible?","authors":"Yulia B. Monakhova*, Klaudia Adels and Bernd W.K. Diehl, ","doi":"10.1021/acs.chemrestox.4c0039810.1021/acs.chemrestox.4c00398","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00398https://doi.org/10.1021/acs.chemrestox.4c00398","url":null,"abstract":"To circumvent regulatory frameworks, many producers start to substitute plant-derived nicotine (tobacco-derived nicotine, TDN) by synthetic nicotine (tobacco-free nicotine, TFN) in e-cigarette products. Due to the higher costs of enantiomeric synthesis and purification of TFN, there is a need to develop an analytical method that clearly distinguishes between the two sources. To trace nicotine's origin, its enantiomeric purity can be postulated by 1H NMR spectroscopy using (R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (BNPPA) as a chiral complexing agent. Low-field (LF) NMR conditions were optimized for this purpose even using a small amount of e-liquid sample (limit of quantification 8 mg/mL nicotine). All investigated products were found to contain one isomer (most likely (S)-(−)-nicotine). A direct 13C NMR method at natural abundance has been validated to differentiate (S)-TDN and (S)-TFN in e-cigarettes produced using nicotine of different origin. The method is based on calculation of the relative 13C content of 10 C-positions of the nicotine molecule with intraday and interday precisions below <0.2%. The method was applied to 12 commercial e-cigarette products labeled as containing TDN and TFN. Principal component analysis (PCA) was applied to the relative peak areas to visualize the difference between studied products. The LF 1H NMR method is a good alternative to expensive high-field NMR to differentiate between a racemate mixture and single optical isomers, whereas only high-precision 13C NMR can be used to distinguish (S)-TDN and (S)-TFN in e-cigarettes after appropriate sample extraction.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"2022–2031 2022–2031"},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850173","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

Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-15 DOI: 10.1021/acs.chemrestox.4c0035710.1021/acs.chemrestox.4c00357

Jiannan Zheng, Guode Zhao, Zixia Hu, Chenyang Jia, Weiwei Li*, Ying Peng* and Jiang Zheng*,

{"title":"Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4","authors":"Jiannan Zheng, Guode Zhao, Zixia Hu, Chenyang Jia, Weiwei Li*, Ying Peng* and Jiang Zheng*, ","doi":"10.1021/acs.chemrestox.4c0035710.1021/acs.chemrestox.4c00357","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00357https://doi.org/10.1021/acs.chemrestox.4c00357","url":null,"abstract":"Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer’s disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC–MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"2003–2012 2003–2012"},"PeriodicalIF":3.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842934","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

Capturing Differential Quality of Experimental Evidence in a Predictive Quantum-Mechanical Model for Respiratory Sensitization 在呼吸敏化量子力学预测模型中捕捉不同质量的实验证据

IF 3.7 3区医学

Chemical Research in Toxicology Pub Date : 2024-11-14 DOI: 10.1021/acs.chemrestox.4c0028910.1021/acs.chemrestox.4c00289

Jakub Kostal*, Joshua Vaughan, Kamila Blum and Adelina Voutchkova-Kostal,

{"title":"Capturing Differential Quality of Experimental Evidence in a Predictive Quantum-Mechanical Model for Respiratory Sensitization","authors":"Jakub Kostal*, Joshua Vaughan, Kamila Blum and Adelina Voutchkova-Kostal, ","doi":"10.1021/acs.chemrestox.4c0028910.1021/acs.chemrestox.4c00289","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00289https://doi.org/10.1021/acs.chemrestox.4c00289","url":null,"abstract":"Asthma is of concern in occupational toxicology with significant public-health and economic costs. In the absence of benchmark in vivo and in vitro tests, the use of mechanistically sound in silico models is critical to inform hazard and to protect workers from exposure to potentially harmful substances. We recently reported on the computer-aided discovery and REdesign (CADRE) model for respiratory sensitization, which relies on a tiered structure of expert rules, molecular simulations, quantum-mechanics calculations and advanced statistics to accurately identify respiratory sensitizers from first principles. Here, we present an update to this model based on two years of testing in the pharmaceutical space, where we captured the heterogeneity of the underlying experimental evidence in two predictive tiers, thus allowing the practitioner to select an outcome based on their expert assessment of the data reliability and relevance. This user-based tuning of predictive models is critical for end points that lack consensus on what constitutes satisfactory evidence to support a decision in the handling of chemicals for occupational safety.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1944–1951 1944–1951"},"PeriodicalIF":3.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843281","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