Archives of Toxicology最新文献

{"title":"Oxidative stress-driven disease-associated microglia (DAM)-like polarization in human microglia (HMC3) cells exposed to small-size silver nanoparticles in a transwell co-culture system with neurons (cholinergic differentiated SH-SY5Y) cells in vitro.","authors":"Bartosz Skóra, Konrad A Szychowski","doi":"10.1007/s00204-025-04183-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04183-0","url":null,"abstract":"<p><p>Silver nanoparticles (AgNPs) are well-established pro-oxidative and pro-inflammatory factors, with the strongest effects observed in smaller NPs. This is particularly important due to the increasing accumulation of AgNPs in the environment and the human food chain in recent years. This accumulation has been correlated with an increased number of neurodegenerative diseases, in which microglia-driven inflammation plays a pivotal role. Importantly, the disease-associated microglia (DAM) phenotype has gained special attention. Therefore, this study aimed to determine the role of small-size AgNPs in inducing a DAM-like phenotype in a transwell co-culture model of human microglia (HMC3) and neurons (differentiated SH-SY5Y) in vitro. Our results demonstrated time- and dose-dependent cytotoxicity of small-size AgNPs in both tested cell models. Moreover, in the transwell co-culture system of HMC3 and differentiated SH-SY5Y cells, exposure to AgNPs led to ROS-dependent inflammation, associated with TLR4 and NF-κB activation, subsequently upregulating DAM-related proteins (e.g., ICAM1, ITGAX, ApoE, and B2M). A time-dependent increase in ^•NO levels was also observed. Notably, reduced SYN1 and SNAP-25 expression, along with increased CAT, SOD, TRAF6, and TLR4 expression in differentiated SH-SY5Y cells, indicates ROS- and inflammation-mediated neuronal dysfunction. These findings indicate that the use of small-size AgNPs should be reconsidered due to their potential neurotoxic effects, but further investigation is necessary in future, using in vivo models.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074228","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":"Ontogeny of drug-induced fatty liver disease (DIFLD): from key initiating events to disease phenotypes.","authors":"Ernesto López-Pascual, Marta Moreno-Torres, Erika Moro, Anna Rapisarda, Rita Ortega-Vallbona, Eva Serrano-Candelas, Rafael Gozalbes, Ramiro Jover, José V Castell","doi":"10.1007/s00204-025-04178-x","DOIUrl":"https://doi.org/10.1007/s00204-025-04178-x","url":null,"abstract":"<p><p>We conducted an expert review of clinical case reports on drug-induced fatty liver disease (DIFLD) to classify drugs according to distinct clinical phenotypes. Seven clusters were identified based on clinical, biochemical, and histological features reflecting drug toxic mechanisms: Cluster 0 (Control): Drugs with no known steatotic effects or clinical evidence of DIFLD. Cluster 1: Drugs with mild pro-steatotic effects, exacerbating existing metabolic steatosis without significant liver enzyme elevation. Cluster 2: Compounds causing moderate steatosis with mild hepatocellular damage, occasional enzyme increases, and delayed onset. Cluster 3: Agents causing severe mitochondrial dysfunction, ATP depletion, and lactic acidosis, initially without inflammation. Cluster 4: Drugs inducing inflammatory steatohepatitis with moderate elevations of liver enzymes (ALT, AST, ALP 90-700 U/L) but preserved liver function. Cluster 5: Drugs causing severe steatohepatitis with marked enzyme elevation (ALT, AST > 700 U/L) indicating significant liver injury and inflammation. Cluster 6: Compounds causing steatohepatitis with additional cholestasis and elevated bilirubin (> 11 mg/dL). Clusters 1 and 2 primarily impair β-oxidation and mitochondrial respiration, linked to high lipophilicity and typically lower daily doses. Cluster 3 involves mitochondrial DNA depletion and impaired lipid export. Clusters 4 and 5 combine mitochondrial and nuclear receptor disruption, often linked to higher daily doses. Cluster 6 combines steatosis-promoting mechanisms with bile acid transport disruption. This classification improves understanding of DIFLD phenotypes by linking clinical manifestations with drug physicochemical properties and toxicological mechanisms, aiding diagnosis and risk assessment of drug-induced steatosis.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074243","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":"The pyrrolizidine alkaloid lasiocarpine impairs cell cycle progression in vitro.","authors":"Stefanie Hessel-Pras, Marlena Beckschulte, Antonia Peters, Anja Koellner, Beatrice Rosskopp, Aaron Stahl, Markus Templin, Heike Sprenger, Linda Boehmert, Jan-Heiner Kuepper, Benjamin Sachse, Bernd Schaefer","doi":"10.1007/s00204-025-04185-y","DOIUrl":"10.1007/s00204-025-04185-y","url":null,"abstract":"<p><p>1,2-Unsaturated pyrrolizidine alkaloids (PA) induce severe acute and chronic hepatotoxicity. Effects include an impairment of the cell cycle. To elucidate this effect, cell cycle progression was analyzed by flow cytometry, changes in cell and nucleus size, differential gene expression and protein phosphorylation patterns of regulatory key proteins in the Chinese hamster lung fibroblast cell line V79 and/or the human hepatoblastoma cell line HepG2, both overexpressing human CYP3A4 (V79_3A4/HepG2_3A4). Lasiocarpine, a potent PA representative, reduced the cell viability of human CYP3A4-overexpressing cell lines concentration-dependently. Microscopic observation showed a marked increase in cell and nucleus size of V79_3A4 cells after exposure to 10 µM lasiocarpine. In the human CYP3A4-overexpressing cell lines, cells accumulate in G₂/M phase after lasiocarpine treatment. Based on these findings, the gene expression pattern of cell cycle-related genes was investigated in HepG2_3A4 cells showing a decrease of e. g. WEE1, and CHEK1 and an increase of PAK1 and ATM. While results on cell cycle regulation at the level of gene expression are of limited relevance, protein phosphorylation plays an important role. Therefore, we also elucidated the protein phosphorylation status of regulatory key proteins. The results clearly indicate an induction of the DNA damage response and a late G2 arrest. In conclusion, an impairment of the cell cycle was observed. It correlates with the metabolic activation of lasiocarpine and is most likely mediated by adduct formation of the reactive pyrrole esters with DNA, leading to a disruption of cellular homeostasis and genomic instability.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068912","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":"Sorption processes of wastewater contaminants on virgin and aged polystyrene microplastics: physicochemical changes and cellular toxicity assessment.","authors":"Antonio Laganà, Consuelo Celesti, Daniela Iannazzo, Alessio Facciolà, Carmelina Anzalone, Angela Di Pietro, Giuseppa Visalli","doi":"10.1007/s00204-025-04153-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04153-6","url":null,"abstract":"<p><p>Microplastics (MPs) are pervasive pollutants, subject to environmental ageing processes. This enhances their capacity to adsorb various contaminants from environmental matrices, posing growing threats to both ecosystems and human health. This study investigates the adsorption behaviour and cytotoxicity of 1 μm polystyrene microplastics (mPS), both virgin (v-mPS) and home-aged by thermo-oxidation (ox-mPS), following exposure to wastewater (ww). Hydrodynamic diameter measurements and FTIR analysis revealed significant adsorption of organic and inorganic substances onto v- and ox-mPS, proving the formation of an environmental corona. Approximately, 25% of the entire oxidisable load of the ww, assessed by COD, was adsorbed to the mPS. ww-v-mPS exhibited a higher increase in particle size and a thicker coating due to their hydrophobic nature and affinity for apolar or weakly polar compounds. Conversely, ww-ox-mPS, enriched with polar functional groups, displayed a more moderate increase in diameter. Zeta potential measurements indicated significant adsorption of negatively charged species on v-mPS. In human colorectal cells, both ww-mPS caused cell mortality increases (%Δ 243.3 and 83.2 in v- and ox-mPS in comparison to untreated mPS), highlighting potential risks from ingestion of contaminated food.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063433","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":"Developmental neurotoxicity of organophosphate flame retardants (OPFRs): risks to human health and ecosystems.","authors":"Furong Zhang, Ruifang Liu, Jianwei Lou, Fuyong Song","doi":"10.1007/s00204-025-04184-z","DOIUrl":"https://doi.org/10.1007/s00204-025-04184-z","url":null,"abstract":"<p><p>Organophosphate flame retardants (OPFRs), widely used as primary alternatives to banned brominated flame retardants, have been extensively applied across various industries worldwide. In recent years, OPFRs have increasingly emerged as significant environmental pollutants and have been shown to possess potential developmental neurotoxicity. This review systematically synthesizes current research on their environmental distribution, bioaccumulation, and neurodevelopmental effects. Studies indicate OPFRs are widely detected in air, water, soil, and organisms, demonstrating high environmental persistence and mobility. Humans are exposed through inhalation, ingestion, and dermal absorption, with infants and young children at higher risk due to frequent hand-to-mouth behavior and prolonged indoor exposure. Epidemiological studies suggest that prenatal exposure to OPFRs may be associated with low birth weight, behavioral abnormalities, and cognitive deficits, with evidence of sex-specific susceptibility. Experimental studies using model organisms, such as zebrafish and rodents, have further elucidated the potential mechanisms underlying OPFR-induced developmental neurotoxicity. Chemicals such as TDCPP, TPhP, and TCEP have been found to disrupt neural cell proliferation and differentiation, dysregulate gene expression, induce neuroinflammation, increase oxidative stress, and impair endocrine homeostasis. Despite significant progress in understanding the toxicity of OPFRs, critical scientific challenges remain unresolved. For example, the long-term effects of low-dose OPFR exposure on the nervous system are not yet fully understood. Furthermore, there is a lack of systematic analysis regarding the combined effects of multiple pollutants. Therefore, a deeper understanding of the toxicological mechanisms of OPFRs is essential to provide a stronger scientific foundation for the formulation of evidence-based environmental and public health policies.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051345","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":"Insights into the molecular mechanism of neurological diseases and their pathophysiological responses","authors":"Sharmistha Banerjee,&nbsp;Parames C. Sil","doi":"10.1007/s00204-025-04181-2","DOIUrl":"10.1007/s00204-025-04181-2","url":null,"abstract":"<div><p>The origin of neurological disorders and their associated symptoms have been known for a very long time tracing to the origin of human being. However, the detailed mechanism at the molecular level came to existence after intensive research for decades. This review aims to discuss the molecular mechanisms responsible for the onset till the progression of these diseases casting its role at cellular, organelles, and metal ions level. Advanced microscopic techniques enabled correlation of pathological responses at ultrastructural level that is helpful if coupled with biochemical parameters. The review also sheds a glimpse of focus on creative movements to improve cognition in neurodegenerative patients as a part of therapy.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 11","pages":"4367 - 4383"},"PeriodicalIF":6.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051486","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":"Identification of small GTPases as potential target proteins of the mycotoxin and renal carcinogen ochratoxin A.","authors":"Borchers Johannes, Perugino Florinda, Schlosser Andreas, Lamer Stephanie, Lutz Leonie, Pedroni Lorenzo, Dellafiora Luca, Angela Mally","doi":"10.1007/s00204-025-04189-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04189-8","url":null,"abstract":"<p><p>Ochratoxin A (OTA), a mycotoxin commonly found as a contaminant in a variety of foods, is known for its ability to cause kidney damage and tumors in rodents. Recent research indicates that replicative stress leading to aberrant mitoses and subsequent genetic instability may play a key role in OTA carcinogenicity. However, the specific molecular targets of OTA and early key events leading to replicative stress and mitotic disruption remain to be determined. In this study, a chemoproteomic workflow was employed to identify proteins that directly interact with OTA and its non-chlorinated analog ochratoxin B (OTB). To this end, OTA and OTB were immobilized on a stationary phase through covalent coupling to amine-functionalized agarose beads via their carboxy group. OTA-and OTB-functionalized beads were then incubated with kidney epithelial cell lysates to capture binding proteins for subsequent analysis via tandem mass spectrometry. Protein mass spectrometry identified several members of the family of small GTPases as specific OTA- and OTB-binding proteins. Moreover, a 3D molecular modeling approach integrating docking and molecular dynamics simulations was applied to study the mycotoxin-protein complex stability over time, providing mechanistic insights from an atomistic point of view. Ras superfamily GTPases, which were previously demonstrated to be transcriptionally deregulated in the presence of OTA, play crucial roles in various cellular functions, including DNA replication, mitosis, protein transport and cell adhesion, thus offering plausible links to cellular effects observed in response to OTA. In summary, results from this study for the first time identify small GTPases as direct molecular targets of OTA and suggest a potential role of small GTPases in OTA toxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063337","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":"Evaluating the use of rodents as in vitro, in vivo and ex vivo experimental models for the assessment of tyrosine kinase inhibitor-induced cardiotoxicity: a systematic review.","authors":"Lucy Gill, Amy Chadwick, Annette P Meeson, Richard Barrett-Jolley, Marie M Phelan, Rachel A Oldershaw","doi":"10.1007/s00204-025-04159-0","DOIUrl":"https://doi.org/10.1007/s00204-025-04159-0","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) are widely used in cancer therapy yet are strongly associated with acute and chronic cardiotoxicity in patients. There is a critical need to advance our understanding of the pathophysiology that underlies TKI-mediated cardiotoxicity, and central to this is the use of reproducible and relevant preclinical models, which are employed in the evaluation of TKIs across the drug discovery pipeline. We have conducted a systematic review of the literature to determine how rodent models are used in the measurement of TKI-induced cardiotoxicity, focusing on animal reports, physiological cardiac outputs, histopathology, and biomarkers. A PRISMA-compliant systematic review was conducted using PubMed, Scopus, and Web of Science to identify studies reporting on TKI-induced cardiotoxicity in rodents. Only controlled in vivo, primary in vitro, and ex vivo studies using rats, mice, hamsters or guinea pigs were included. Data were extracted on species, strain, sex, age, experimental design, and cardiac outcomes with risk of bias analyses performed using the SYRCLE and SciRAP tools. Among 92 studies, sunitinib, imatinib, and sorafenib were the most frequently examined TKIs, with cardiotoxicity exhibited as altered cardiac functional parameters, fibrotic changes, arrhythmias, and elevated cardiac biomarkers. Rats (51 studies) and mice (46 studies) were predominantly used to study the effects of TKIs, whilst guinea pigs were underrepresented, limiting insights into electrophysiological changes that are associated with cardiotoxicity. Most studies used male rodents, and only two studies assessed age-related effects. Comparison between species strains was rarely conducted, despite evidence of this being a contributing factor to pre-disposition to cardiotoxicity. Rodent models were shown to replicate TKI-induced cardiotoxic effects observed in humans, but risk of bias analyses revealed limited evidence for study randomisation, inconsistent blinding, lack of sex-balanced studies, and poor strain diversity. Poor methodological quality and reporting across studies compromised reproducibility and interpretation of clinical relevance. Our study highlights the need for implementation of standardised protocols, strain, sex and age-stratified analyses to better support preclinical-to-clinical translation, as well as improve the safety of TKIs for patients and ensure more ethical use of animals in research.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038891","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":"Inhibitory effects of 6-O-palmitoyl-L-ascorbic acid (ASC16) on the enzymatic activity of Bothrops alternatus venom.","authors":"Franco Maslovski, Jaime Andrés Pereañez, David Hernández, María Alonso, Silvina Echeverría, Carolina Gay, Laura Leiva, Emilio Angelina, Luciano Fusco","doi":"10.1007/s00204-025-04188-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04188-9","url":null,"abstract":"<p><p>In the anti-venom production process, it is essential to use whole venom during immunization to generate specific antibodies capable of neutralizing all venom components. However, efforts are being made to improve the traditional immunization process by reducing the toxic effects of venom components on the immunized animals while ensuring an optimal immune response in accordance with good manufacturing practices. In this context, we aimed to evaluate the capacity of ASC16 to inhibit the enzymatic activity of the main components of B. alternatus venom. In vitro studies were conducted to evaluate the inhibitory effect of ASC16 on metalloproteinases (SVMP), serine proteinases (SVSP) and phospholipases A₂ (PLA₂) using specific substrates. In vivo assays measured edema-forming activity, and histological analysis with hematoxylin and eosin staining were performed. Additionally, hemorrhage inhibition was tested using a murine model. In silico studies were also carried out using bothropasin as a model. The results of enzyme inhibition showed that ASC16 significantly inhibited SVMP (49.31% ± 0.62), SVSP (63.11 ± 3.86%) and PLA₂ activity (36.52% ± 0.09). ASC16 did not reduce edema but it significantly inhibited hemorrhage (66.32%). In silico analysis suggested that ASC16's hydrophobic portion binds to critical residues involved in catalysis of the SVMP (Glu146 and His145), while the hydrophilic fraction also interacts with the protein (Pro109, Thr110, Gly112, and Tyr132). These findings position ASC16 as a promising candidate for use as an additive inhibitor in adjuvant formulations in antivenom immunization schemes for B. alternatus.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038977","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":"First multifaceted ADME profile of ACP-105 (CAS: 1048998-11-3): a novel non-steroidal selective androgen receptor modulator used as doping in sports-integrative in silico toxicological studies for clinical and forensic toxicology purposes.","authors":"Oktawia Fijałkowska, Kamil Jurowski","doi":"10.1007/s00204-025-04170-5","DOIUrl":"10.1007/s00204-025-04170-5","url":null,"abstract":"<p><p>ACP-105 (CAS: 1048998-11-3) is a novel non-steroidal selective androgen receptor modulator (SARM), increasingly detected in anti-doping analyses, yet lacking a comprehensive ADME profile. This study provides the first integrative in silico characterization of ACP-105's ADME properties using seven independent methods (ADMETlab 3.0, ADMET Predictor 12.0, ACD/Percepta, SwissADME, pkCSM, XenoSite and DruMAP). The compound demonstrated high gastrointestinal absorption (up to 100%), moderate lipophilicity (LogP 3.0-3.52), low solubility (LogS ~ - 4.1 to - 4.4), and Caco-2 permeability ranging from 13.6 to 152 × 10^-6 cm/s. It shows strong plasma protein binding (77-99%), minimal free plasma fraction (< 1%), and variable tissue distribution (Vd 0.18-12 L/kg). Blood-brain barrier penetration was predicted in most models. Metabolic profiling identified six metabolites (M1-M6), primarily formed via CYP3A4, with additional contributions from CYP2C9, CYP2C19, and CYP2D6. ACP-105 is a consistent substrate for CYP3A4 (82-100%) and likely undergoes stable and unstable oxygenation, N-dealkylation, and UGT conjugation. Interactions with DNA/protein and potential cyanide release were also predicted. Clearance predictions varied (7.175-3.86 × 10^-5 mL/min/kg), with a short half-life (~ 1.18 h), and no OCT2-mediated renal excretion expected. These findings provide a foundational ADME profile of ACP-105, essential for interpreting exposure in clinical toxicology and supporting evidence in forensic investigations involving illicit use.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028839","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}