Chemico-Biological Interactions最新文献

{"title":"Organotins as inhibitors targeting human and rat steroid 5α-reductase 1: structure-activity relationship and docking analysis","authors":"Shufang Qi ,&nbsp;Rong Cui ,&nbsp;Wanyu Li ,&nbsp;Jin Yang ,&nbsp;Ke Zheng ,&nbsp;Shaowei Wang ,&nbsp;Ren-Shan Ge ,&nbsp;Han Lin ,&nbsp;Yiyan Wang","doi":"10.1016/j.cbi.2025.111637","DOIUrl":"10.1016/j.cbi.2025.111637","url":null,"abstract":"<div><div>Steroid 5α-reductase 1 (SRD5A1) catalyzes the conversion of testosterone to dihydrotestosterone, playing crucial roles in steroidogenesis in the brain and reproductive system. This study aimed to systematically evaluate the inhibitory effects and mechanisms of action of organotins on human and rat SRD5A1. Sixteen organotins were screened for the inhibitory strength and enzyme inhibition assays, molecular docking, and correlation analyses were performed. Among the tested compounds, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin significantly inhibited human SRD5A1 with IC₅₀ values of 30.31, 17.83, 28.28, 12.69, and 4.38 μM, respectively. Dioctyltin, tributyltin, tetrapropyltin, and tributylphenyltin also markedly inhibited rat SRD5A1 with IC₅₀ values ranging from 11.91 to 29.96 μM. These organotins exhibited mixed/noncompetitive inhibition with respect to testosterone and bound to the NADPH-binding site of SRD5A1, forming interactions with critical methionine residues. Dithiothreitol partially reversed inhibition by triphenyltin, suggesting that interaction with the sulfhydryl group of methionine mediates inhibition. In SF126 cells, diphenyltin, triphenyltin, and triethyltin significantly reduced dihydrotestosterone production at ≥ 1 μM. Correlation analysis indicated that molecular weight, heavy atoms, and LogP were correlated with inhibitory potency against SRD5A1. These findings elucidate the structure-activity relationships and mechanisms by which organotins inhibit SRD5A1, highlighting their potential to disrupt steroidogenesis and neurosteroid biosynthesis, with implications for reproductive and neurological health.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111637"},"PeriodicalIF":4.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shiga toxins from enterohemorrhagic Escherichia coli and anti-GB3 antibody as novel agents against triple negative breast cancer","authors":"Alipio Pinto ,&nbsp;Noelia V. Miret ,&nbsp;Ana Belen Ramos Aloi ,&nbsp;Florencia Vassallu ,&nbsp;Lionel M. Igaz ,&nbsp;Andrea S. Randi ,&nbsp;Jorge Goldstein","doi":"10.1016/j.cbi.2025.111639","DOIUrl":"10.1016/j.cbi.2025.111639","url":null,"abstract":"<div><div>Shiga toxins (Stx) are potent bacterial exotoxins and the main virulence factor of enterohemorrhagic <em>Escherichia coli.</em> Stx have ribotoxic activity in eukaryotic target cells of the mammalian host by recognizing its globotriaosylceramide receptor (Gb3), which results in rapid protein synthesis inhibition and cell death. Our aim was to study the potential of Stx1, Stx2, and an anti-Gb3 antibody as novel cytotoxic agents against triple negative breast cancer (TNBC) cells. The expression of Gb3 and Stx uptake was analyzed by immunofluorescence (IF) in TNBC MDA-MB-231 and non-tumorigenic mammary epithelial cells NMuMG, using VERO cells as a positive control. Results showed that MDA-MB-231 tumor cells express the Gb3 receptor as much as VERO cells. In addition, MDA-MB-231 ‒but not mammary epithelial cells NMuMG‒ can incorporate Stx2. Cell viability was evaluated through MTT assays, finding that MDA-MB-231 cell viability was reduced by Stx1, Stx2, and anti-Gb3 treatments, while NMuMG cell viability remained unaltered. Both Stx1 and Stx2 reduced proliferation and migration in MDA-MB-231 cells, assessed through BrdU incorporation and the wound healing assay, respectively. The expression levels of LC3 as an autophagy marker increased with Stx1, Stx2, and anti-Gb3 treatments. In all assays, the presence of PPMP, an inhibitor that reduces Gb3 synthesis, blocked the effects produced by Stx. Finally, Stx treatment increased total and nuclear TAR-DNA-binding protein-43 protein expression. These findings suggest that Stx1 and Stx2 are potential new therapeutic agents in TNBC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111639"},"PeriodicalIF":4.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More fraudulent history of cancer risk assessment: The US National Academy of Sciences Biological Effects of Atomic Radiation (BEAR) I Genetics Panel used falsified data greatly exaggerating hereditary/cancer risks","authors":"Edward J. Calabrese ,&nbsp;Paul B. Selby","doi":"10.1016/j.cbi.2025.111640","DOIUrl":"10.1016/j.cbi.2025.111640","url":null,"abstract":"<div><div>This paper reports that data used by the US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel (1956) to estimate risks of hereditary damage in the US population were falsified, greatly exaggerating the risks. These risk estimates were mostly based on the first of many mouse specific-locus experiments of William and Liane Russell, Oak Ridge National Laboratory, which were determined in 1996 to be erroneous by a US Department of Energy (DOE) investigation of scientific misconduct. The basis of the falsification is that William Russell removed data on a large mutation cluster from the control group resulting in a falsely elevated estimate of the induced frequency of radiation-induced gene mutations. While DOE subsequently compelled the Russells to correct the record, these corrections were never retrospectively applied to the Genetics Panel (1956) report, which used the falsified Russell data. Thus, no corrections have been made by the NAS or regulatory agencies, such as the EPA, whose national risk assessment policies/practices for cancer risk assessment were significantly corrupted and overstated by these errors. Based on the discovery reported herein that the Genetics Panel's policy recommendations considerably overestimated hereditary risks based upon Russell-inspired falsified publication, it seems imperative that the Genetics Panel report (1956) published in <em>Science</em> be retracted due to inherent falsification-based inaccuracies that continue to impact governmental regulatory agencies, such as the EPA, and the global community that often rely upon the US NAS and regulatory agencies for guidance, as well as the broader scientific community and general public.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111640"},"PeriodicalIF":4.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Investigation of Hardwickiic Acid-Derived Amides as Potential Cholinesterase Inhibitors: Molecular Docking and ADME/Tox Predictions","authors":"Rayssa Ribeiro ,&nbsp;Franco H.A. Leite ,&nbsp;Géssica O. Mendes ,&nbsp;Fernanda Georgia de F. T. Barbosa ,&nbsp;Samir F.A. Cavalcante ,&nbsp;Tanos C.C. Franca ,&nbsp;Marcelo C. Santos ,&nbsp;Valdir F. Veiga-Junior","doi":"10.1016/j.cbi.2025.111631","DOIUrl":"10.1016/j.cbi.2025.111631","url":null,"abstract":"<div><div>This study is a theoretical investigation of amides derived from hardwickiic acid (<strong>HA</strong>) as potential inhibitors of human acetyl- and butyryl-cholinesterase (hAChE and hBChE) and as drug candidates against Alzheimer's Disease (AD). Twelve compounds were prepared and geometrically optimized using GaussView 5.0.8 and the DFT method with the B3LYP/6-31G basis set to visualize molecular electrostatic potential (MEP) maps and frontier orbitals (HOMO and LUMO). In addition, pharmacokinetic and toxicological properties were studied using the online servers PreADMET and SwissADME. Molecular docking was performed against crystal structures of hAChE and hBChE prepared with the biopolymer module in SYBYL-X 2.0, previously validated. The results revealed similar profiles in surface maps and molecular orbitals for the amide substituent group. Pharmacokinetic predictions demonstrated that all 12 <strong>HA</strong> amide derivatives showed significant values for blood-brain barrier (BBB) penetration, classifying them as active in the central nervous system (CNS), a crucial pathway for AD treatment. Intermolecular interactions between the compounds and targets suggest that the benzyl amide derivative <strong>I</strong> had the highest affinity toward the hAChE binding site (−10.1 kcal/mol), while the hydroxy amide derivative <strong>L</strong> showed the highest affinity for the hBChE binding site (−9.7 kcal/mol). These findings can inform future enzymatic assays of <strong>HA</strong> amide derivatives against AChE and BChE.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111631"},"PeriodicalIF":4.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin prevents axitinib-induced kidney damage in mice","authors":"Na Niu ,&nbsp;Xu Li ,&nbsp;Dong Tang ,&nbsp;Tian-Qing Jin ,&nbsp;Si-Wen Ji ,&nbsp;Chun-Lei Yu ,&nbsp;Yong Li","doi":"10.1016/j.cbi.2025.111628","DOIUrl":"10.1016/j.cbi.2025.111628","url":null,"abstract":"<div><div>Axitinib, a tyrosine kinase inhibitor (TKI) with antiangiogenic effects, is used in anticancer therapy. Axitinib can cause dose-limiting adverse reactions such as proteinuria and renal function impairment, but the mechanisms remain unclear. This study aims to elucidate the mechanism of axitinib-induced proteinuria and potential intervention strategies. We employed C57BL/6 mice as the primary subjects, administering axitinib (50 mg/kg/day) for 1 week, along with luteolin (100 mg/kg/day) to observe its protective effects. Our findings demonstrated that axitinib induced elevated urinary protein and creatinine levels in C57BL/6 mice, resulting in pathological changes in glomeruli, including thickened glomerular basement membrane (GBM), podocyte foot process effacement, disruption of the filtration slit diaphragm structure, and collagen deposition. Axitinib significantly reduced the protein expression of podocyte filtration barrier core functional proteins (nephrin, podocin, and podocalyxin) and upregulated transient receptor potential channel 6 (TRPC6) expression. Pharmacological inhibition of TRPC6 with SAR7334 alleviated axitinib-induced downregulation of these core proteins. Luteolin exerts a protective effect and demonstrates a stable binding conformation with TRPC6 along with high binding affinity. Our results elucidate that axitinib induces podocyte filtration barrier core protein loss, foot process effacement, glomerulosclerosis, and proteinuria through upregulation of TRPC6 protein expression. Additionally, naturally derived luteolin serves as a potential intervention strategy, providing a theoretical basis for the clinical prevention and treatment of nephrotoxicity caused by axitinib and other TKIs.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111628"},"PeriodicalIF":4.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic activation and cytotoxicity of bavachin mediated by CYP3A in mice","authors":"Tingmin Ye ,&nbsp;Chunping Tang ,&nbsp;Dandan Yang ,&nbsp;Qing Zhang ,&nbsp;Yufen Liao ,&nbsp;Jie Dai ,&nbsp;Hong Tang ,&nbsp;Changqiang Ke ,&nbsp;Ying Peng ,&nbsp;Yang Ye ,&nbsp;Weiwei Li ,&nbsp;Jiang Zheng","doi":"10.1016/j.cbi.2025.111630","DOIUrl":"10.1016/j.cbi.2025.111630","url":null,"abstract":"<div><div>Bavachin (BVC), a flavonoid, is found in <em>Psoraleae fructus</em> (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase (ALT) and aspartate transaminase (AST) in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or <em>N</em>-acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding <em>o</em>-quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH <em>in vivo</em> and that BVC contributes to the depletion of hepatic GSH caused by PF extract.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"419 ","pages":"Article 111630"},"PeriodicalIF":4.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential modulation of ionotropic glutamate receptors by glufosinate ammonium, the glutamate-mimetic","authors":"Ye-Ji Kim ,&nbsp;Hye-Won Lim ,&nbsp;Dong Ho Woo","doi":"10.1016/j.cbi.2025.111629","DOIUrl":"10.1016/j.cbi.2025.111629","url":null,"abstract":"<div><div>Although glufosinate ammonium (GLA) is known to affect hyperexcitability, neurodevelopment, and psychiatric disorders via ionotropic glutamate receptor (iGluR) activation, its detailed mechanisms remain unclear. This study characterizes the effects of GLA on the activity of N-methyl-<span>d</span>-aspartate receptor (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in rat primary neuron cultures and their membrane expression. GLA activated GluA1 L497Y, a desensitization mutant and a glutamate sensor, but did not activate the γ-aminobutyric acid (GABA) c channel, a GABA sensor. GLA inhibited NMDAR-mediated current in the presence of glutamate/glycine and facilitated AMPAR-mediated current in the presence of glutamate. GLA activated NMDAR-mediated Ca²⁺ transients in the absence of glutamate and inhibited NMDAR-mediated Ca²⁺ transients in the presence of glutamate in HEK 293 cells expressing NMDAR, indicating that GLA acts similarly to glutamate. Moreover, GLA reduced the frequency of excitatory post-synaptic current (EPSC_NMDAR) and EPSC_AMPAR at synapses. Additionally, GLA induced AMPAR-mediated steady-state inward currents. Furthermore, it is noteworthy that GLA treatment caused neuronal death after 24 h but not after 5 h of incubation. After 5 h treatment, NMDAR expression preferentially declined, while AMPAR expression enhanced, as measured by the intensity of GluN1 and GluA1 in somas and processes. These results were consistent with reduced NMDAR-mediated Ca²⁺ transients and increased AMPAR-mediated Ca²⁺ transients. This is the first report to demonstrate the onset mechanism of GLA on NMDAR and AMPAR before neuronal death. These findings provide insight into understanding neurotoxicity and potential therapeutic targets for mitigating GLA-induced damage.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111629"},"PeriodicalIF":4.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential cardiotoxic components of Tripterygium wilfordii Hook. f. prediction and verification through cardiac ion channel proteins","authors":"Jianfang Sun ,&nbsp;Yujie Fan ,&nbsp;Xiaoya Li ,&nbsp;Yingxin Qiu ,&nbsp;Yuying Lu ,&nbsp;Zhuo Shen ,&nbsp;Jinghai Zhang ,&nbsp;Mingyi Zhao ,&nbsp;Yijia Xu","doi":"10.1016/j.cbi.2025.111627","DOIUrl":"10.1016/j.cbi.2025.111627","url":null,"abstract":"<div><div><em>Tripterygium wilfordii</em> Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, the application is limited by some potential toxicity and side effects. Therefore, this study aimed to explore the potential heart risk components and potential mechanism of <em>Tripterygium wilfordii</em>. Traditional Chinese Medicine Database and Analysis Platform (TCMSP), Swiss Target Prediction, GeneCards and Open Target Platform databases were used to obtain the potential targets of <em>Tripterygium wilfordii</em> monomers and arrhythmia. GO pathway enrichment analysis was performed by Sangerbox. The potential interaction between monomers and hNav1.5 and hERG (two subtypes of ion channel protein) were predicted by AutoDock and verified by using whole cell patch clamp recordings. Intracellular calcium concentration of H9c2 myocardial cells were tested Fura2-AM fluorescence probe. Acute toxicity tests in mice were used to verify the potential cardiac risk <em>in vivo</em> through heart rate and representative cardiac enzyme profile. The results showed that 38 kinds of <em>Tripterygium wilfordii</em> components were screened by TCMSP, among them, 17 terpenoid monomer structures were acquired through PubChem database. 119 genes associated with disease and monomers were also obtained through various databases, and GO function analysis suggested that ion channels are probably target types of cardiac risk. The molecular docking results showed that 17 components could bind with hNav1.5 and hERG with different binding energy. Patch clamp results showed that mairin and wilforlide A could significantly inhibit the peak current of both hNav1.5and hERG and affect the dynamic property of both channels. Furthermore, mairin and wilforlide A could inhibit cell viability and increase intracellular calcium concentration of H9c2 myocardial cells, and mairin inhibited the heart rate ratio and increased the level of CK-MB. In conclusion, ion channel might be the potential cardiac risk target of <em>Tripterygium wilfordii</em> terpenoid, and mairin and wilforlide A might be main components of <em>Tripterygium wilfordii</em> causing cardiac risk.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111627"},"PeriodicalIF":4.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotoxic risks of long-term environmental exposure to pesticides: a review","authors":"Yumeng Leng ,&nbsp;Ye Zeng ,&nbsp;Yuning Zhang ,&nbsp;Jialin Zhang ,&nbsp;Hao Xin ,&nbsp;Mingyang Hou ,&nbsp;Siman Ma ,&nbsp;Hong Zhang","doi":"10.1016/j.cbi.2025.111626","DOIUrl":"10.1016/j.cbi.2025.111626","url":null,"abstract":"<div><div>Pesticides are chemical substances that prevent pests, control weeds, sterilize, and regulate plant growth. Although mechanized spraying of pesticides significantly improves operational efficiency, excessive use and improper handling of pesticides can lead to environmental pollution, resulting in long-term exposure of nontarget organisms and causing toxicity, particularly neurotoxicity in these organisms. This review summarizes the toxic effects of long-term pesticide exposure on various neurological functions, providing insights for future studies on pesticide exposure. Furthermore, it discusses the role of pesticide exposure in the pathogenesis of neurological and psychiatric disorders and serves as a reference for the prevention, treatment, and management of neurotoxicity resulting from long-term pesticide exposure. The findings are expected to inspire future research aimed at mitigating environmental pollution and enhancing the quality of life for nontarget organisms in the environment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111626"},"PeriodicalIF":4.7,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resolving data gaps in the acute toxicity profile of phosgene oxime (CX): a comprehensive in silico evaluation","authors":"Maciej Noga ,&nbsp;Kamil Jurowski","doi":"10.1016/j.cbi.2025.111623","DOIUrl":"10.1016/j.cbi.2025.111623","url":null,"abstract":"<div><div>Phosgene oxime (CX) is a highly reactive chemical warfare agent classified as a nettle agent due to its rapid induction of corrosive skin lesions, severe pain, and tissue necrosis upon exposure. Despite its recognised extreme toxicity, substantial gaps remain in our understanding of CX's acute toxicological profile, primarily owing to limited experimental data stemming from significant ethical, safety, and regulatory constraints. Consequently, accurate risk assessment for CX exposure has been challenging, necessitating the application of alternative predictive methodologies. In response, this study aimed to comprehensively evaluate the acute toxicity of CX via state-of-the-art <em>in silico</em> methods that integrate multiple computational toxicology tools, including STopTox, ADMETlab, admetSAR, TEST, ProTox-III, VEGA, OPERA, the QSAR Toolbox, and Percepta ACD/Labs. Predictive modelling encompasses acute oral, dermal, and inhalation toxicity endpoints, providing theoretical LD₅₀/LC₅₀ values for rats, which are extrapolated to human-equivalent doses via established allometric scaling techniques. The results consistently demonstrated a high acute toxicity profile of CX across all exposure routes, particularly via inhalation and dermal contact, emphasizing the substantial health risks associated with potential CX incidents. However, notable variability among computational predictions has led to limitations related to the applicability domain and dataset constraints, highlighting areas requiring further methodological refinement. This research represents the extensive application of validated <em>in silico</em> approaches to elucidate the acute toxicity parameters of CX. These findings underscore the utility of computational toxicology methodologies as ethically sound, hypothesis-generating alternatives to experimental testing, enhancing chemical threat preparedness and regulatory toxicological assessment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"418 ","pages":"Article 111623"},"PeriodicalIF":4.7,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}