{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:46:02Z","timestamp":1792565162132,"version":"4.5.0"},"reference-count":53,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82174070"],"award-info":[{"award-number":["82174070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Food and Chemical Toxicology"],"published-print":{"date-parts":[[2026,12]]},"DOI":"10.1016\/j.fct.2026.116413","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:11:09Z","timestamp":1790781069000},"page":"116413","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Paired CYP1A2\/3A4-HepG2 phenotyping supports machine-learning classification of literature-curated hepatotoxicity categories"],"prefix":"10.1016","volume":"218","author":[{"given":"Er-Chong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Tong","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Ning","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Lu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.fct.2026.116413_bib1","series-title":"Proceedings of the 25th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining (KDD \u201919)","first-page":"2623","article-title":"Optuna: a next-generation hyperparameter optimization framework","author":"Akiba","year":"2019"},{"key":"10.1016\/j.fct.2026.116413_bib2","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.3390\/biomedicines13112722","article-title":"Drug-metabolizing gene expression identity: comparison across liver tissues and model cell lines","volume":"13","author":"Arzumanian","year":"2025","journal-title":"Biomedicines"},{"key":"10.1016\/j.fct.2026.116413_bib3","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1021\/tx800407w","article-title":"Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction","volume":"22","author":"Bauman","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib4","doi-asserted-by":"crossref","first-page":"9860","DOI":"10.1038\/s41467-025-65690-3","article-title":"A large-scale human toxicogenomics resource for drug-induced liver injury prediction","volume":"16","author":"Bergen","year":"2025","journal-title":"Nat. Commun."},{"key":"10.1016\/j.fct.2026.116413_bib5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0041-008X(03)00128-5","article-title":"An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons","volume":"189","author":"Brandon","year":"2003","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"10.1016\/j.fct.2026.116413_bib6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"10.1016\/j.fct.2026.116413_bib7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1517\/17425255.2.2.183","article-title":"Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies","volume":"2","author":"Castell","year":"2006","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"issue":"7","key":"10.1016\/j.fct.2026.116413_bib54","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1038\/ajg.2014.131","article-title":"ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury","volume":"109","author":"Chalasani","year":"2014","journal-title":"American Journal of Gastroenterology"},{"key":"10.1016\/j.fct.2026.116413_bib9","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1038\/s41596-023-00840-9","article-title":"Optimizing the cell painting assay for image-based profiling","volume":"18","author":"Cimini","year":"2023","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.fct.2026.116413_bib10","doi-asserted-by":"crossref","first-page":"6395","DOI":"10.1038\/s41467-023-41948-6","article-title":"A systematic study of key elements underlying molecular property prediction","volume":"14","author":"Deng","year":"2023","journal-title":"Nat. Commun."},{"key":"10.1016\/j.fct.2026.116413_bib11","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3390\/antiox10010106","article-title":"High-content screening for the detection of drug-induced oxidative stress in liver cells","volume":"10","author":"Donato","year":"2021","journal-title":"Antioxidants"},{"key":"10.1016\/j.fct.2026.116413_bib12","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1016\/j.jhep.2019.02.014","article-title":"EASL clinical practice guidelines: drug-induced liver injury","volume":"70","year":"2019","journal-title":"J. Hepatol."},{"key":"10.1016\/j.fct.2026.116413_bib13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2165\/00002018-200932010-00005","article-title":"Drug-induced liver injury network (DILIN) prospective study: rationale, design and conduct","volume":"32","author":"Fontana","year":"2009","journal-title":"Drug Saf."},{"key":"10.1016\/j.fct.2026.116413_bib14","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1021\/acs.jafc.2c07206","article-title":"Metabolic activation of pesticide isoprocarb mediated by CYP3A4 and the possible correlation with its cytotoxicity","volume":"71","author":"Guan","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.fct.2026.116413_bib15","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1021\/tx700079z","article-title":"Cytochrome P450 and chemical toxicology","volume":"21","author":"Guengerich","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.drudis.2023.103621","article-title":"Preclinical evaluation of chemically reactive metabolites and mitigation of bioactivation in drug discovery","volume":"28","author":"He","year":"2023","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.fct.2026.116413_bib17","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1007\/s00204-024-03701-w","article-title":"Prediction of cytochrome P450-mediated bioactivation using machine learning models and in vitro validation","volume":"98","author":"Hu","year":"2024","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib18","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.3390\/ijms22062843","article-title":"Bioluminescence measurement of time-dependent dynamic changes of CYP-mediated cytotoxicity in CYP-expressing luminescent HepG2 cells","volume":"22","author":"Iwado","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.fct.2026.116413_bib19","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.livres.2019.10.002","article-title":"Mitochondrial damage and biogenesis in acetaminophen-induced liver injury","volume":"3","author":"Jaeschke","year":"2019","journal-title":"Liver Res"},{"key":"10.1016\/j.fct.2026.116413_bib20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1021\/tx050267h","article-title":"Human cytochrome P450 enzymes of importance for the bioactivation of methyleugenol to the proximate carcinogen 1\u2032-hydroxymethyleugenol","volume":"19","author":"Jeurissen","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev-pharmtox-010814-124720","article-title":"Predicting toxicities of reactive metabolite-positive drug candidates","volume":"55","author":"Kalgutkar","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib22","doi-asserted-by":"crossref","first-page":"727","DOI":"10.3390\/toxics13090727","article-title":"Utilizing multiple behavioral endpoints to identify negative control chemicals in a larval zebrafish behavior assay","volume":"13","author":"Knapp","year":"2025","journal-title":"Toxics"},{"key":"10.1016\/j.fct.2026.116413_bib23","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2131\/jts.44.347","article-title":"Transcriptional profiling of cytochrome P450 genes in the liver of adult zebrafish, Danio rerio","volume":"44","author":"Kubota","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"10.1016\/j.fct.2026.116413_bib24","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11481-021-09990-7","article-title":"Lysosomal stress response (LSR): physiological importance and pathological relevance","volume":"16","author":"Lakpa","year":"2021","journal-title":"J. Neuroimmune Pharmacol."},{"key":"10.1016\/j.fct.2026.116413_bib25","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1021\/tx5000409","article-title":"Reactive metabolite trapping screens and potential pitfalls: bioactivation of a homomorpholine and formation of an unstable thiazolidine adduct","volume":"27","author":"Lenz","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib26","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.toxlet.2009.02.012","article-title":"Cytotoxicity of ginkgolic acid in HepG2 cells and primary rat hepatocytes","volume":"187","author":"Liu","year":"2009","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.fct.2026.116413_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.aquatox.2020.105540","article-title":"Inducibility of cytochrome P450-mediated 7-methoxycoumarin-O-demethylase activity in zebrafish (Danio rerio) embryos","volume":"225","author":"Loerracher","year":"2020","journal-title":"Aquat. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib28","first-page":"4765","article-title":"A unified approach to interpreting model predictions","volume":"30","author":"Lundberg","year":"2017","journal-title":"Adv. Neural Inf. Process. Syst."},{"key":"10.1016\/j.fct.2026.116413_bib29","doi-asserted-by":"crossref","first-page":"861","DOI":"10.21105\/joss.00861","article-title":"UMAP: uniform manifold approximation and projection for dimension reduction","volume":"3","author":"McInnes","year":"2018","journal-title":"J. Open Source Softw."},{"key":"10.1016\/j.fct.2026.116413_bib30","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3390\/ph13120456","article-title":"Cytochrome P450 expression and chemical metabolic activity before full liver development in zebrafish","volume":"13","author":"Nawaji","year":"2020","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.fct.2026.116413_bib31","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3390\/cells11101677","article-title":"Generation of HepG2 cells with high expression of multiple drug-metabolizing enzymes for drug discovery research using a PITCh system","volume":"11","author":"Negoro","year":"2022","journal-title":"Cells"},{"key":"10.1016\/j.fct.2026.116413_bib32","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12916-016-0553-2","article-title":"Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature","volume":"14","author":"Onakpoya","year":"2016","journal-title":"BMC Med."},{"key":"10.1016\/j.fct.2026.116413_bib33","doi-asserted-by":"crossref","first-page":"4319","DOI":"10.1038\/s41598-024-54634-4","article-title":"Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products","volume":"14","author":"Park","year":"2024","journal-title":"Sci. Rep."},{"key":"10.1016\/j.fct.2026.116413_bib34","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.drudis.2020.10.010","article-title":"Artificial intelligence in drug discovery and development","volume":"26","author":"Paul","year":"2021","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.fct.2026.116413_bib35","first-page":"2825","article-title":"Scikit-learn: machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"10.1016\/j.fct.2026.116413_bib36","doi-asserted-by":"crossref","first-page":"4493","DOI":"10.1007\/s00204-025-04139-4","article-title":"Nutrient environment improves drug metabolic activity in human iPSC-derived hepatocytes and HepG2","volume":"99","author":"Pozo Garcia","year":"2025","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib37","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1007\/s00204-017-2002-1","article-title":"Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury","volume":"91","author":"Proctor","year":"2017","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00204-024-03886-0","article-title":"Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury","volume":"99","author":"Qian","year":"2025","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib39","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-0039-1679919","article-title":"Acetaminophen hepatotoxicity","volume":"39","author":"Ramachandran","year":"2019","journal-title":"Semin. Liver Dis."},{"key":"10.1016\/j.fct.2026.116413_bib40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2131\/jts.41.1","article-title":"Xenobiotic metabolism in the zebrafish: a review of the spatiotemporal distribution, modulation and activity of cytochrome P450 families 1 to 3","volume":"41","author":"Saad","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"10.1016\/j.fct.2026.116413_bib41","doi-asserted-by":"crossref","DOI":"10.3390\/ijms232315116","article-title":"Methotrexate-induced liver injury is associated with oxidative stress, impaired mitochondrial respiration, and endoplasmic reticulum stress in vitro","volume":"23","author":"Schmidt","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.fct.2026.116413_bib42","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41592-024-02528-8","article-title":"Cell painting: a decade of discovery and innovation in cellular imaging","volume":"22","author":"Seal","year":"2025","journal-title":"Nat. Methods"},{"key":"10.1016\/j.fct.2026.116413_bib43","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1021\/acs.chemrestox.5b00410","article-title":"Reactive metabolites: current and emerging risk and hazard assessments","volume":"29","author":"Thompson","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib44","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1007\/s00204-015-1503-z","article-title":"High-content screening technology for studying drug-induced hepatotoxicity in cell models","volume":"89","author":"Tolosa","year":"2015","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib45","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s00204-013-1012-x","article-title":"HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved","volume":"87","author":"Tolosa","year":"2013","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib46","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s00204-017-2036-4","article-title":"Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury","volume":"92","author":"Tolosa","year":"2018","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib47","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-pharmtox-010510-100514","article-title":"Bioactivation of drugs: risk and drug design","volume":"51","author":"Walsh","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"10.1016\/j.fct.2026.116413_bib48","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.3390\/molecules27092647","article-title":"Fraxinellone induces hepatotoxicity in zebrafish through oxidative stress and the transporters pathway","volume":"27","author":"Wang","year":"2022","journal-title":"Molecules"},{"key":"10.1016\/j.fct.2026.116413_bib49","doi-asserted-by":"crossref","first-page":"8243","DOI":"10.1021\/acs.jafc.9b02137","article-title":"Role of metabolic activation in elemicin-induced cellular toxicity","volume":"67","author":"Wang","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"10.1016\/j.fct.2026.116413_bib50","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/clpt.2011.63","article-title":"Drug safety sciences and the bottleneck in drug development","volume":"89","author":"Watkins","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"10.1016\/j.fct.2026.116413_bib51","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cbi.2015.10.009","article-title":"Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity","volume":"255","author":"Xuan","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"10.1016\/j.fct.2026.116413_bib52","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.fct.2026.116413_bib53","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A simple statistical parameter for use in evaluation and validation of high-throughput screening assays","volume":"4","author":"Zhang","year":"1999","journal-title":"J. Biomol. Screen"}],"container-title":["Food and Chemical Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0278691526004886?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0278691526004886?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:18:30Z","timestamp":1792563510000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0278691526004886"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,12]]},"references-count":53,"alternative-id":["S0278691526004886"],"URL":"https:\/\/doi.org\/10.1016\/j.fct.2026.116413","relation":{},"ISSN":["0278-6915"],"issn-type":[{"value":"0278-6915","type":"print"}],"subject":[],"published":{"date-parts":[[2026,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Paired CYP1A2\/3A4-HepG2 phenotyping supports machine-learning classification of literature-curated hepatotoxicity categories","name":"articletitle","label":"Article Title"},{"value":"Food and Chemical Toxicology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.fct.2026.116413","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"116413"}}