Xenobiotica最新文献

{"title":"Protective role of Algerian <i>Myrtus communis</i> L. against pesticide mixture-induced reproductive toxicity: a combined experimental and molecular dynamics insights targeting steroidogenesis pathway.","authors":"Samia Belahcene, Essaid Leghouchi, Faizul Azam, Gagandeep Singh, Nabil Adrar, Inessa Telezhnikova, Suliman A Almahmoud, Widad Kebsa","doi":"10.1080/00498254.2026.2673543","DOIUrl":"10.1080/00498254.2026.2673543","url":null,"abstract":"<p><p>This study aims to assess the impact of myrtle methanolic extract (Mex) in mitigating imidacloprid (Imi) and chlorothalonil (Chl)-induced prostate and testicular dysfunction in rats after 28 days of oral exposure.High-performance liquid chromatography coupled with ultraviolet-visible spectroscopy analysis (HPLC/UV-Vis) identified 12 compounds, with flavonols (40.23%), phenolic acids (33.19%), and flavanols (21.58%) as the main classes. Testosterone (T) and follicle-stimulating hormone (FSH) levels dropped sharply in the Imi + Chl group.Redox impairment was marked by mitochondrial swelling in groups that received Imi, Chl, or both individually or in combination. In contrast, Mex combined with the Imi + Chl mixture significantly restored these alterations to normal levels. Histopathological analysis of the prostate further confirmed these effects.Pesticides and bioactive compounds from Mex were docked into key enzymes involved in steroid biosynthesis, followed by MD simulations. Molecular mechanics/generalized born surface area (MMGBSA) binding energies indicated that rutin and epigallocatechin gallate (EGCG) from Mex-50 may compete with pesticides for the active sites of aromatase and steroid 5-alpha reductase type-II (SRD5A2), offering significant protection to the steroid biosynthesis pathway.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"381-400"},"PeriodicalIF":1.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147934011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meeting report of the 6th European Biotransformation Workshop.","authors":"M Ahlqvist, M Walles, E M Isin, L Laboureur, A Pähler","doi":"10.1080/00498254.2026.2671853","DOIUrl":"10.1080/00498254.2026.2671853","url":null,"abstract":"<p><p>Workshop Overview: Challenges, strategies, and emerging technologies in the field of biotransformation were presented and discussed at the Sixth European Biotransformation Workshop, held on September 1, 2025, at Churchill College in Cambridge, UK.Purpose of the Report: This meeting report provides a summary of the key presentations and discussions that took place during the workshop.Topics Covered: The workshop addressed several major themes, including recent advances in developmental biotransformation applications using Accelerator Mass Spectrometry (AMS), new approach methodologies (NAMs) and regulatory guidance for assessing human metabolites, and the development of new in vitro systems to evaluate metabolism and toxicity.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"359-364"},"PeriodicalIF":1.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147875566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo preclinical pharmacokinetic characterisation of ulacamten, a small molecule cardiac myosin inhibitor for the treatment of heart failure with preserved ejection fraction (HFpEF).","authors":"Mark P Grillo, Jeanelle Zamora, Ashton N Easterday, Mina Azimi, Roxanne J Romond, Bradley P Morgan, Rajaa Sukhun","doi":"10.1080/00498254.2026.2668393","DOIUrl":"10.1080/00498254.2026.2668393","url":null,"abstract":"<p><p>Ulacamten, a targeted cardiac myosin inhibitor designed for the treatment of heart failure with preserved ejection fraction (HFpEF), was characterised in <i>in vitro</i> and <i>in vivo</i> preclinical assays.Ulacamten human hepatic clearance was predicted to be 5.7 mL/min/kg from <i>in vitro</i> metabolic stability studies in human liver microsomes. For human, plasma protein binding was moderate at 58.5% bound, whole blood-to-plasma partitioning ratio was 0.93, and ulacamten showed high permeability and no significant efflux in a Caco-2 cell-line.Ulacamten clearance <i>in vivo</i> across species was low-to-moderate with 9.33, 37.3, 7.57, and 11.6 mL/min/kg in mouse, rat, dog, and monkey, respectively. Volume of distribution ranged from 4.23 L/kg in dog to 8.89 L/kg in monkey. Oral bioavailability ranged from 12.6% in mouse to 51.4% in monkey.The predominant ulacamten metabolic pathways <i>in vitro</i> included CYP-mediated deformylation (metabolite M1) and hydroxylation of the methyl group of the methylcyclohexyl moiety (metabolite M2).The predicted human pharmacokinetic parameters clearance (CL), steady-state volume of distribution, and half-life were 4.5 mL/min/kg, 5.8 L/kg, and 14.9-hours, respectively, determined from an average of multiple prediction methods.Ulacamten preclinical attributes and predicted human pharmacokinetic parameters allowed for its progression to clinical development.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"365-380"},"PeriodicalIF":1.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Size-dependent toxicity of microplastics and nanoplastics: insights from the <i>Drosophila melanogaster</i> model.","authors":"Yuqing Dong, Meijun Pang, Ying Li, Jingyi Li, Chao Zhang, Guolei Sun, Mingxiang Chang, Yiwen Wang","doi":"10.1080/00498254.2026.2671851","DOIUrl":"10.1080/00498254.2026.2671851","url":null,"abstract":"<p><p>Microplastics and nanoplastics (MNPs) are ubiquitous environmental pollutants that enter organisms and induce multi-system damage. Particle size is a critical determinant of MNPs' bioavailability, biodistribution, and toxic intensity, with smaller particles exhibiting stronger biopermeability and toxic hazards. <i>Drosophila melanogaster</i> (fruit fly) has emerged as an ideal model organism for investigating MNPs' toxic mechanisms due to its short life cycle, clear genetic background, and high genetic homology with humans.This review systematically summarises research on the toxicity of MNPs with different sizes based on the <i>Drosophila</i> model, clarifying the size-dependent toxicity pattern. Large microplastics (1-5 mm) remain in the digestive tract, causing local physical damage and dysbiosis. Small microplastics (1 μm-1 mm) induce intestinal damage, oxidative stress, as well as abnormalities in behaviour and reproduction. Submicroplastics (100 nm-1 μm) can penetrate the intestinal barrier, triggering systemic inflammation and cardiac dysfunction. Nanoplastics (<100 nm) possess the strongest biopermeability, invading cells and organelles to cause DNA damage, immune disorders, and transgenerational toxicity, while also exacerbating synergistic toxicity with heavy metals via 'carrier effects'.This review provides a theoretical basis for MNP risk assessment and highlights the unique value of the <i>Drosophila</i> model in this field.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"414-423"},"PeriodicalIF":1.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic therapeutic effect and mechanism of Cryptotanshinone combined with Matrine on ovarian cancer.","authors":"Haiying Xu, Yanli Zhao, Anqi Zhu, Jing Peng, Min Zhong","doi":"10.1080/00498254.2026.2668390","DOIUrl":"10.1080/00498254.2026.2668390","url":null,"abstract":"<p><p>Chemotherapy resistance in ovarian cancer (OC) poses a significant challenge in clinical treatment. We aim to explore the inhibitory impact of the synergistic action of Cryptotanshinone and matrine on OC cells, along with its molecular mechanism, thereby providing a novel therapeutic strategy for OC management. Cell proliferation was assessed via the CCK-8 assay; apoptosis was analysed by flow cytometry; cell migration and invasion were evaluated using the Transwell assay; gene expression was measured with qRT-PCR. A nude mouse xenograft model was established to verify in vivo efficacy. The role of the PI3K/Akt/mTOR pathway was elucidated through rescue experiments. Cyptotanshinone and matrine inhibited OC cell proliferation in a dose- and time-dependent manner. Combination therapy synergistically enhanced the antiproliferative effects, inducing apoptosis, suppressing migration and invasion, and downregulating the expression of MMP2 and MMP9. In cisplatin-resistant cells, the combination reversed drug resistance and reduced P-gp expression. Mechanistically, the combination markedly downregulated transcription of key genes in the PI3K/Akt/mTOR pathway. Rescue experiments confirmed that pathway inhibition underpins the synergistic effect. Cryptotanshinone and matrine exert anti-OC effects through multiple mechanisms by inhibiting the PI3K/Akt/mTOR pathway, effectively reversing drug resistance.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"443-452"},"PeriodicalIF":1.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the components of hepatotoxicity induced by <i>Senecio scandens</i> Buch.-Ham. based on integrated network toxicology, metabolomics, and <i>in vivo</i> experiments.","authors":"Shunjun Yang, Hongxin Wang, Bowen Gong, Rong Tan, Ying Liu, Tiantai Wu, Yunfang Jiang, Qing Rao, Weiwei Li, Jia Yu, Chang Lin, Yang Jin, Shiyu Zhang","doi":"10.1080/00498254.2026.2668400","DOIUrl":"10.1080/00498254.2026.2668400","url":null,"abstract":"<p><strong>Background: </strong>1. <i>Senecio scandens</i> Buch.-Ham. (SBH) is widely used in traditional Chinese medicine, yet its clinical application is constrained by hepatotoxic pyrrolizidine alkaloids (PAs). The relative toxic contributions of individual PAs in SBH and their <i>in vivo</i> metabolic consequences remain unclear.</p><p><strong>Purpose: </strong>2. This study sought to elucidate PAs-related hepatotoxicity of SBH by integrating network toxicology, LC-MS/MS fingerprinting, <i>in vivo</i> toxicity evaluation, and liver metabolomics.</p><p><strong>Methods: </strong>3. Network toxicology and molecular docking were used to prioritise hepatotoxic PAs and their putative targets. LC-MS/MS fingerprints of major PAs in 12 SBH samples were established. Spectrum-toxicity correlation analysis and untargeted metabolomics were used to assess hepatotoxicity-related associations and SPL-induced metabolic perturbations.</p><p><strong>Results: </strong>4. SPL, senecionine, adonifoline, and senkirkine were prioritised as candidate hepatotoxic PAs, with CYP3A4/CYP2C9 and DNA adduct-related pathways highlighted as potentially relevant toxicological nodes. Considerable regional variation in PAs levels was observed across SBH samples. Acute SBH exposure caused marked liver injury, and spectrum-toxicity modelling indicated that SPL showed the strongest association with hepatotoxicity among the detected PAs. Metabolomic profiling further showed that SPL exposure was associated with alterations in lipid and bile acid metabolism, glutathione metabolism, and the pentose phosphate pathway, together with enrichment of xenobiotic metabolism by cytochrome P450 and chemical carcinogenesis-DNA adduct pathways.</p><p><strong>Conclusion: </strong>5. SPL is closely associated with SBH-induced hepatotoxicity and produces a metabolic signature consistent with canonical PAs bioactivation. Although SPL appears to be the most influential PAs among those detected, definitive comparisons of toxic potency require further validation using equimolar pure-compound exposure models.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"401-413"},"PeriodicalIF":1.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An In silico model-based feasibility assessment of erlotinib long-acting injectable formulation for the management of metastatic non-small cell lung cancer.","authors":"Anumol Joseph, Sideequl Akbar, Adarsh Malgave, Rutuja Suryawanshi, Rajkumar Malayandi","doi":"10.1080/00498254.2026.2661623","DOIUrl":"10.1080/00498254.2026.2661623","url":null,"abstract":"<p><p>Erlotinib is an orally administered tyrosine kinase inhibitor used in the treatment of EGFR-positive non-small cell lung cancer. However, poor tolerability and suboptimal patient adherence often limit its clinical efficacy. Furthermore, lower doses are recommended for elderly patients, those with EGFR-sensitising mutations, and cutaneous toxicities. A PLGA-based long-acting injectable formulation may offer significant advantages for metastatic NSCLC by enhancing treatment compliance. This study aims to develop a physiologically based pharmacokinetic model to support dose selection, optimisation of release profiles, and dosage form design.The semimechanistic ERL PBPK model was first developed and validated for oral formulations and subsequently extended to intramuscular depots. The IM model was used to determine the optimal dose and release profile to maintain plasma drug concentrations above the IC50 and Css _min targets.A monthly dose of 750 mg with an intermediate-release profile able to maintain the drug concentration above the C_{ss, min}. When targeting the IC₅₀, the prototype formulations required a monthly dose of 300 mg and a three-month dose of 1200 mg, both with intermediate-release profiles.The semimechanistic PBPK model successfully predicted the optimal dose and release profile. The results provided valuable insights for polymer grade selection and drug-to-polymer ratio optimisation.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"295-309"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Richard Tecwyn Williams - the Birmingham years (1934-1942).","authors":"Steve Mitchell, Rosemary Waring","doi":"10.1080/00498254.2026.2652053","DOIUrl":"10.1080/00498254.2026.2652053","url":null,"abstract":"<p><p>Richard Tecwyn Williams is acclaimed for being amongst the founders of the systematic study of foreign compound metabolism. His chemically-oriented collation of peripheral and often unappreciated metabolic observations, together with his own researches, helped to engineer a new field of study.Although researchers travel along a pathway, inevitable interaction with colleagues, unique circumstances and unforeseen opportunities will buffet the journey until a suitable niche appears. A vocation emerges, drawn out as it may be but nevertheless, dictating the future direction. This sequence was to occur during Williams' time at Birmingham University.At Birmingham, Williams entered a transitional period in his scientific career. From initially continuing his work on glucuronic acid, he progressed through phenols and various monoterpenes to the metabolism of sulphonamides, slowly changing his initial focus on conjugating agents themselves to their broader role in the metabolic fate of xenobiotics.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"265-271"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linalool, linalyl acetate, and lavender essential oil: evaluation of metabolism and drug interactions using canine liver microsomes and recombinant enzymes.","authors":"Raquel Rodrigues Soares-Santos, Benito Soto-Blanco, Renata Cristina Mendes Ferreira, Michael H Court","doi":"10.1080/00498254.2026.2654087","DOIUrl":"10.1080/00498254.2026.2654087","url":null,"abstract":"<p><p>Pharmacokinetic interactions between natural extracts and hepatic cytochrome P450 (CYP) enzymes are a concern in veterinary medicine. Lavender essential oil (LEO), containing linalool (LIN) and linalyl acetate (LINAc), may be coadministered with conventional medicines.This study examined the canine metabolism of LIN and LINAc by substrate depletion using pooled dog liver microsomes (pDLMs) and recombinant canine CYP enzymes (rCYPs). Inhibitory effects of LIN, LINAc, and LEO on CYP isoform-selective probe drug reactions were also evaluated.LINAc was hydrolysed to LIN by a heat-sensitive esterase activity in pDLMs. LIN depletion by pDLMs was NADPH-dependent, saturable with a Michaelis-Menten constant of 52 ± 11 µM, and induced by over 5-fold in liver microsomes from phenobarbital-treated dogs. Recombinant CYP2B11 showed the highest LIN depletion activity, followed by CYP2C21, while other CYPs tested did not show measurable substrate depletion. Inhibition experiments showed that LIN, LINAc, and LEO inhibited CYP2B11-mediated metabolism but not metabolism by CYP2C21, CYP2D15, or CYP3A12. IC₅₀ values for LIN, LINAc, and LEO were 7.1, 2.7, and 2.5 µM for tramadol N-demethylation, and 13.9, 8.0, and 8.6 µM for methadone-N-demethylation, respectively. None of the terpenes were shown to directly inhibit recombinant CYP2B11 activity, suggesting that they exerted indirect inhibition <i>via</i> metabolites generated by other CYPs in pDLMs.These findings highlight CYP2B11 and CYP2C21 as key enzymes in LIN and LINAc metabolism and underscore the potential for herb-drug interactions when treating dogs with lavender essential oil.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"282-294"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond hemorrhagic cystitis: unraveling the multifaceted protective roles of sodium 2-mercaptoethanesulfonate.","authors":"Prathap Srirangan, Muthukumar Balakrishnan, Shalini Magesh, Mukul Shyam, Abilash Valsala Gopalakrishnan, Sabina Evan Prince","doi":"10.1080/00498254.2026.2653829","DOIUrl":"10.1080/00498254.2026.2653829","url":null,"abstract":"<p><p>Sodium 2-mercaptoethanesulfonate (MESNA) is widely used as a uroprotective agent to prevent haemorrhagic cystitis (HC) associated with oxazaphosphorine chemotherapy; however, emerging evidence suggests broader cytoprotective potential beyond the urinary system.This review systematically compiles and evaluates preclinical and clinical evidence on the multi-organ protective effects of MESNA, including its roles in mitigating nephrotoxicity, hepatotoxicity, cardiotoxicity, neurotoxicity, pulmonary injury, gastrointestinal damage, and reproductive toxicity.The protective mechanisms of MESNA are primarily attributed to its thiol-mediated detoxification, antioxidant activity, and anti-inflammatory effects, including scavenging of reactive oxygen species (ROS), reduction of lipid peroxidation, modulation of cytokine responses, and maintenance of cellular redox balance.In addition to its established clinical use in oncology, MESNA demonstrates potential applications in surgical procedures, ischemia-reperfusion injury, and combination therapies, although current clinical evidence supporting its systemic protective effects remains limited.Despite its promising therapeutic profile, factors such as short plasma half-life, limited systemic bioavailability, and variability in clinical outcomes highlight the need for further mechanistic studies and well-designed clinical trials to establish its role as a multi-organ cytoprotective agent.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"318-338"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}