Chemical Research in Toxicology最新文献

{"title":"Production of Peroxymonocarbonate by Steady-State Micromolar H2O2 and Activated Macrophages in the Presence of CO2/HCO3– Evidenced by Boronate Probes","authors":"Edlaine Linares,&nbsp;Divinomar Severino,&nbsp;Daniela R. Truzzi,&nbsp;Natalia Rios,&nbsp;Rafael Radi and Ohara Augusto*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00059","DOIUrl":"10.1021/acs.chemrestox.4c00059","url":null,"abstract":"<p >Peroxymonocarbonate (HCO₄^–/HOOCO₂^–) is produced by the reversible reaction of CO₂/HCO₃^– with H₂O₂ (<i>K</i> = 0.33 M^–1, pH 7.0). Although produced in low yields at physiological pHs and H₂O₂ and CO₂/HCO₃^– concentrations, HCO₄^– oxidizes most nucleophiles with rate constants 10 to 100 times higher than those of H₂O₂. Boronate probes are known examples because HCO₄^– reacts with coumarin-7-boronic acid pinacolate ester (CBE) with a rate constant that is approximately 100 times higher than that of H₂O₂ and the same holds for fluorescein-boronate (Fl-B) as reported here. Therefore, we tested whether boronate probes could provide evidence for HCO₄^– formation under biologically relevant conditions. Glucose/glucose oxidase/catalase were adjusted to produce low steady-state H₂O₂ concentrations (2–18 μM) in Pi buffer at pH 7.4 and 37 °C. Then, CBE (100 μM) was added and fluorescence increase was monitored with time. The results showed that each steady-state H₂O₂ concentration reacted more rapidly (∼30%) in the presence of CO₂/HCO₃^– (25 mM) than in its absence, and the data permitted the calculation of consistent rate constants. Also, RAW 264.7 macrophages were activated with phorbol 12-myristate 13-acetate (PMA) (1 μg/mL) at pH 7.4 and 37 °C to produce a time-dependent H₂O₂ concentration (8.0 ± 2.5 μM after 60 min). The media contained 0, 21.6, or 42.2 mM HCO₃^– equilibrated with 0, 5, or 10% CO₂, respectively. In the presence of CBE or Fl-B (30 μM), a time-dependent increase in the fluorescence of the bulk solution was observed, which was higher in the presence of CO₂/HCO₃^– in a concentration-dependent manner. The Fl-B samples were also examined by fluorescence microscopy. Our results demonstrated that mammalian cells produce HCO₄^– and boronate probes can evidence and distinguish it from H₂O₂ under biologically relevant concentrations of H₂O₂ and CO₂/HCO₃^–.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445547","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":"Immunological Drug–Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies","authors":"Sophie Grice*,&nbsp;Anna Olsson-Brown,&nbsp;Dean J. Naisbitt and Sean Hammond,&nbsp;","doi":"10.1021/acs.chemrestox.4c00067","DOIUrl":"10.1021/acs.chemrestox.4c00067","url":null,"abstract":"<p >With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug–drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441763","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":"In Vitro Metabolism and p53 Activation of Genotoxic Chemicals: Abiotic CYP Enzyme vs Liver Microsomes","authors":"Luise Henneberger*,&nbsp;Julia Huchthausen,&nbsp;Jenny Braasch,&nbsp;Maria König and Beate I. Escher,&nbsp;","doi":"10.1021/acs.chemrestox.4c0010110.1021/acs.chemrestox.4c00101","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00101https://doi.org/10.1021/acs.chemrestox.4c00101","url":null,"abstract":"<p >Chemicals often require metabolic activation to become genotoxic. Established test guidelines recommend the use of the rat liver S9 fraction or microsomes to introduce metabolic competence to <i>in vitro</i> cell-based bioassays, but the use of animal-derived components in cell culture raises ethical concerns and may lead to quality issues and reproducibility problems. The aim of the present study was to compare the metabolic activation of cyclophosphamide (CPA) and benzo[<i>a</i>]pyrene (BaP) by induced rat liver microsomes and an abiotic cytochrome P450 (CYP) enzyme based on a biomimetic porphyrine catalyst. For the detection of genotoxic effects, the chemicals were tested in a reporter gene assay targeting the activation of the cellular tumor protein p53. Both chemicals were metabolized by the abiotic CYP enzyme and the microsomes. CPA showed no activation of p53 and low cytotoxicity without metabolic activation, but strong activation of p53 and increased cytotoxicity upon incubation with liver microsomes or abiotic CYP enzyme. The effect concentration causing a 1.5-fold induction of p53 activation was very similar with both metabolization systems (within a factor of 1.5), indicating that genotoxic metabolites were formed at comparable concentrations. BaP also showed low cytotoxicity and no p53 activation without metabolic activation. The activation of p53 was detected for BaP upon incubation with active and inactive microsomes at similar concentrations, indicating experimental artifacts caused by the microsomes or NADPH. The activation of BaP with the abiotic CYP enzyme increased the cytotoxicity of BaP by a factor of 8, but no activation of p53 was detected. The results indicate that abiotic CYP enzymes may present an alternative to rat liver S9 fraction or microsomes for the metabolic activation of test chemicals, which are completely free of animal-derived components. However, an amendment of existing test guidelines would require testing of more chemicals and genotoxicity end points.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001842","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":"CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron","authors":"Xinxin Guo,&nbsp;Mingyu Zhang,&nbsp;Ya Li,&nbsp;Zifang Ding,&nbsp;Minglu Liu,&nbsp;Weiwei Li*,&nbsp;Ying Peng* and Jiang Zheng*,&nbsp;","doi":"10.1021/acs.chemrestox.3c00351","DOIUrl":"10.1021/acs.chemrestox.3c00351","url":null,"abstract":"<p >Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or <i>N</i>-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an <i>N</i>-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141416584","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":"Deoxynivalenol Induces Drp-1-Mediated Mitochondrial Dysfunction via Elevating Oxidative Stress","authors":"Sakshi Mishra,&nbsp;Radhika Kapoor,&nbsp; Sushma,&nbsp;Sonam Kanchan,&nbsp;Gaurav Jha,&nbsp;Divyansh Sharma,&nbsp;Bhawna Tomar and Srikanta Kumar Rath*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00066","DOIUrl":"10.1021/acs.chemrestox.4c00066","url":null,"abstract":"<p >Mitochondrial dysfunction is often linked to neurotoxicity and neurological diseases and stems from oxidative stress, yet effective therapies are lacking. Deoxynivalenol (DON or vomitoxin) is one of the most common and hazardous type-B trichothecene mycotoxins, which contaminates crops used for food and animal feed. Despite the abundance of preliminary reports, comprehensive investigations are scarce to explore the relationship between these fungal metabolites and neurodegenerative disorders. The present study aimed to elucidate the precise role of DON in mitochondrial dynamics and cell death in neuronal cells. Excessive mitochondrial fission is associated with the pathology of several neurodegenerative diseases. Human SH-SY5Y cells were treated with different concentrations of DON (250–1000 ng/mL). Post 24 and 48 h DON treatment, the indexes were measured as follows: generation of reactive oxygen species (ROS), ATP levels, mitochondrial membrane potential, calcium levels, and cytotoxicity in SH-SY5Y cells. The results showed that cytotoxicity, intracellular calcium levels, and ROS in the DON-treated group increased, while the ATP levels and mitochondrial membrane potential decreased in a dose-dependent manner. With increasing DON concentrations, the expression levels of P-Drp-1, mitochondrial fission proteins Mff, and Fis-1 were elevated with reduced activities of MFN1, MFN2, and OPA1, further resulting in an increased expression of autophagic marker LC3 and beclin-1. The reciprocal relationship between mitochondrial damage and ROS generation is evident as ROS can instigate structural and functional deficiencies within the mitochondria. Consequently, the impaired mitochondria facilitate the release of ROS, thereby intensifying the cycle of damage and exacerbating the overall process. Using specific hydroxyl, superoxide inhibitors, and calcium chelators, our study confirmed that ROS and Ca2+-mediated signaling pathways played essential roles in DON-induced Drp1 phosphorylation. Therefore, ROS and mitochondrial fission inhibitors could provide critical research tools for drug development in mycotoxin-induced neurodegenerative diseases.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320093","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":"Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions","authors":"Yu-Xin Shen,&nbsp;Pe-Shuen Lee,&nbsp;Chia C. Wang,&nbsp;Ming-Chu Teng,&nbsp;Jhih-Hong Huang and Hsiu-Fang Fan*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00114","DOIUrl":"10.1021/acs.chemrestox.4c00114","url":null,"abstract":"<p >Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315981","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 Tellurium Metabolite in Broccoli Using Complementary Analyses of Inorganic and Organic Mass Spectrometry","authors":"Shohei Takada,&nbsp;Yoshikazu Yamagishi,&nbsp;Yu-ki Tanaka,&nbsp;Yasumi Anan,&nbsp;Sayaka Nagasawa,&nbsp;Hirotaro Iwase and Yasumitsu Ogra*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00148","DOIUrl":"10.1021/acs.chemrestox.4c00148","url":null,"abstract":"<p >Tellurium (Te) is a chalcogen element like sulfur and selenium. Although it is unclear whether Te is an essential nutrient in organisms, unique Te metabolic pathways have been uncovered. We have previously reported that an unknown Te metabolite (UKTe) was observed in plants exposed to tellurate, a highly toxic Te oxyanion, by liquid chromatography–inductively coupled plasma mass spectrometer (LC–ICP–MS). In the present study, we detected UKTe in tellurate-exposed broccoli (<i>Brassica oleracea var. italica</i>) by LC–ICP–MS and identified it as gluconic acid-3-tellurate (GA-3Te) using electrospray ionization mass spectrometer with quadrupole-Orbitrap detector and tandem MS analysis, the high-sensitivity and high-resolution mass spectrometry for organic compounds. We also found that GA-3Te was produced from one gluconic acid and one tellurate molecule by direct complexation in an aqueous solution. GA-3Te was significantly less toxic than tellurate on plant growth. This study is the first to identify the Te metabolite GA-3Te in plants and will contribute to the investigation of tellurate detoxification pathways. Moreover, gluconic acid, a natural and biodegradable organic compound, is expected to be applicable to eco-friendly remediation strategies for tellurate contamination.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295037","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":"Salidroside Inhibits α-Amanitin-Induced AML-12 Cell Apoptosis via the Regulation of PINK1/Parkin-Mediated Mitophagy and Mitochondrial Function","authors":"Yaxiong Zhou,&nbsp;Juyu Wang,&nbsp;Yu Zhao,&nbsp;Yang Zhao,&nbsp;Jieyan Yang,&nbsp;Kuan Wang,&nbsp;Xiang Liu,&nbsp;Weijie Qu,&nbsp;Limei Zhang* and Xiaolong Gu*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00139","DOIUrl":"10.1021/acs.chemrestox.4c00139","url":null,"abstract":"<p >Poisoning caused by the mushroom <i>Amanita phalloides</i>, due to the toxin α-amanitin, accounts for approximately 90% of food poisoning deaths in China with no specific antidotes. To investigate the role of salidroside (Sal) in α-amanitin (α-AMA)-induced mitophagy, mouse liver cells AML-12 were exposed to α-AMA in the presence of Sal or not. Intracellular reactive oxygen species (ROS) levels were measured using a ROS detection kit, mitochondrial activity was evaluated using a mitochondrial red fluorescent probe kit or JC-1 dye, and protein expression levels of PINK1, Parkin, LC3 II, P62, Bax, Bcl-2, Caspase 3, Cleaved-Caspase 3, PARP I, and Cleaved-PARP I were detected through Western blot. Results demonstrated that α-AMA led to increased intracellular ROS levels, cell apoptosis, and decreased mitochondrial membrane potential. Notably, expression levels of mitophagy-related proteins PINK1, Parkin, and LC3 increased significantly while the P62 protein expression decreased remarkably. Furthermore, Sal reversed the α-AMA-induced decrease in cell viability and mitochondrial membrane potential and increase in intracellular ROS level. In addition, Sal promoted expression levels of PINK1, Parkin, and LC3 II while suppressing the Bax/Bcl-2 ratio, Cleaved-Caspase 3, and Cleaved-PARP I as well as P62. The results above proved that salidroside alleviates α-AMA-induced mouse liver cells damage via promoting PINK1/Parkin-mediated mitophagy and reducing cell apoptosis.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282255","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":"Metabolomics Simultaneously Derives Benchmark Dose Estimates and Discovers Metabolic Biotransformations in a Rat Bioassay","authors":"Elena Sostare,&nbsp;Tara J. Bowen,&nbsp;Thomas N. Lawson,&nbsp;Anne Freier,&nbsp;Xiaojing Li,&nbsp;Gavin R. Lloyd,&nbsp;Lukáš Najdekr,&nbsp;Andris Jankevics,&nbsp;Thomas Smith,&nbsp;Dorsa Varshavi,&nbsp;Christian Ludwig,&nbsp;John K. Colbourne,&nbsp;Ralf J. M. Weber,&nbsp;David M. Crizer,&nbsp;Scott S. Auerbach,&nbsp;John R. Bucher and Mark R. Viant*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00002","DOIUrl":"10.1021/acs.chemrestox.4c00002","url":null,"abstract":"<p >Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent with apical end point BMDs, opening the door to using molecular BMDs to derive human health-based guidance values for chemical exposure. Metabolomics measures the responses of small-molecule endogenous metabolites to chemical exposure, complementing transcriptomics by characterizing downstream molecular phenotypes that are more closely associated with apical end points. The aim of this study was to apply BMD modeling to in vivo metabolomics data, to compare metabolic BMDs to both transcriptional and apical end point BMDs. This builds upon our previous application of transcriptomics and BMD modeling to a 5-day rat study of triphenyl phosphate (TPhP), applying metabolomics to the same archived tissues. Specifically, liver from rats exposed to five doses of TPhP was investigated using liquid chromatography–mass spectrometry and ¹H nuclear magnetic resonance spectroscopy-based metabolomics. Following the application of BMDExpress2 software, 2903 endogenous metabolic features yielded viable dose-response models, confirming a perturbation to the liver metabolome. Metabolic BMD estimates were similarly sensitive to transcriptional BMDs, and more sensitive than both clinical chemistry and apical end point BMDs. Pathway analysis of the multiomics data sets revealed a major effect of TPhP exposure on cholesterol (and downstream) pathways, consistent with clinical chemistry measurements. Additionally, the transcriptomics data indicated that TPhP activated xenobiotic metabolism pathways, which was confirmed by using the underexploited capability of metabolomics to detect xenobiotic-related compounds. Eleven biotransformation products of TPhP were discovered, and their levels were highly correlated with multiple xenobiotic metabolism genes. This work provides a case study showing how metabolomics and transcriptomics can estimate mechanistically anchored points-of-departure. Furthermore, the study demonstrates how metabolomics can also discover biotransformation products, which could be of value within a regulatory setting, for example, as an enhancement of OECD Test Guideline 417 (toxicokinetics).</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260133","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":"Role of the PARP1/NF-κB Pathway in DNA Damage and Apoptosis of TK6 Cells Induced by Hydroquinone","authors":"Haipeng Wu,&nbsp;Huan Tang,&nbsp;Xiangli Zou,&nbsp;Qihao Huang,&nbsp;Shimei Wang,&nbsp;Mingzhu Sun,&nbsp;Zhongming Ye,&nbsp;Huanhuan Wang,&nbsp;Yao Wu,&nbsp;Lei Sun,&nbsp;Yuting Chen* and Huanwen Tang*,&nbsp;","doi":"10.1021/acs.chemrestox.4c00135","DOIUrl":"10.1021/acs.chemrestox.4c00135","url":null,"abstract":"<p >Hydroquinone(HQ) is a widely used industrial raw material and is a topical lightening product found in over-the-counter products. However, inappropriate exposure to HQ can pose certain health hazards. This study aims to explore the mechanisms of DNA damage and cell apoptosis caused by HQ, with a focus on whether HQ activates the nuclear factor-κB (NF-κB) pathway to participate in this process and to investigate the correlation between the NF-κB pathway activation and poly(ADP-ribose) polymerase 1(PARP1). Through various experimental techniques, such as DNA damage detection, cell apoptosis assessment, cell survival rate analysis, immunofluorescence, and nuclear-cytoplasmic separation, the cytotoxic effects of HQ were verified, and the activation of the NF-κB pathway was observed. Simultaneously, the relationship between the NF-κB pathway and PARP1 was verified by shRNA interference experiments. The results showed that HQ could significantly activate the NF-κB pathway, leading to a decreased cell survival rate, increased DNA damage, and cell apoptosis. Inhibiting the NF-κB pathway could significantly reduce HQ-induced DNA damage and cell apoptosis and restore cell proliferation and survival rate. shRNA interference experiments further indicated that the activation of the NF-κB pathway was regulated by PARP1. This study confirmed the important role of the NF-κB pathway in HQ-induced DNA damage and cell apoptosis and revealed that the activation of the NF-κB pathway was mediated by PARP1. This research provides important clues for a deeper understanding of the toxic mechanism of HQ.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258429","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}