{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:43:19Z","timestamp":1788252199594,"version":"build-2803163510"},"reference-count":44,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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":["32202184"],"award-info":[{"award-number":["32202184"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005196","name":"Chinese Academy of Agricultural Sciences","doi-asserted-by":"publisher","award":["1610072025002"],"award-info":[{"award-number":["1610072025002"]}],"id":[{"id":"10.13039\/501100005196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515110678"],"award-info":[{"award-number":["2022A1515110678"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002365","name":"China Agricultural University","doi-asserted-by":"publisher","award":["82304859"],"award-info":[{"award-number":["82304859"]}],"id":[{"id":"10.13039\/501100002365","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Chemico-Biological Interactions"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1016\/j.cbi.2026.112016","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T16:26:00Z","timestamp":1773073560000},"page":"112016","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"special_numbering":"C","title":["Seneciphylline induces hepatotoxicity through mitochondrial apoptosis: mechanistic elucidation and in vitro-to-in vivo prediction via physiologically based pharmacokinetic modeling-facilitated reverse dosimetry"],"prefix":"10.1016","volume":"431","author":[{"given":"Yu-Shun","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Li","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Zhong","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Biao","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"1","key":"10.1016\/j.cbi.2026.112016_bib1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s00204-020-02921-0","article-title":"Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites","volume":"95","author":"He","year":"2021","journal-title":"Arch. Toxicol."},{"issue":"4","key":"10.1016\/j.cbi.2026.112016_bib2","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1111\/jgh.14612","article-title":"Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome","volume":"34","author":"Zhuge","year":"2019","journal-title":"J. Gastroenterol. Hepatol."},{"key":"10.1016\/j.cbi.2026.112016_bib3","article-title":"Genotoxicity of selected pyrrolizidine alkaloids in human hepatoma cell lines HepG2 and Huh6","volume":"861\u2013862","author":"Hadi","year":"2021","journal-title":"Mutat. Res., Genet. Toxicol. Environ. Mutagen."},{"issue":"4","key":"10.1016\/j.cbi.2026.112016_bib4","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.jfda.2017.09.001","article-title":"Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid-oxides","volume":"25","author":"He","year":"2017","journal-title":"J. Food Drug Anal."},{"key":"10.1016\/j.cbi.2026.112016_bib5","series-title":"Relative Hepatotoxocity, Carcinogenicity, and Toxicogenomics of Select Dehydropyrrolizidine Alkaloids in Mice","first-page":"1","author":"Clayton","year":"2023"},{"key":"10.1016\/j.cbi.2026.112016_bib6","doi-asserted-by":"crossref","DOI":"10.1016\/j.foodchem.2020.127472","article-title":"Rapid identification and determination of pyrrolizidine alkaloids in herbal and food samples via direct analysis in real-time mass spectrometry","volume":"334","author":"Chen","year":"2021","journal-title":"Food Chem."},{"issue":"11","key":"10.1016\/j.cbi.2026.112016_bib7","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1002\/jat.4004","article-title":"Seneciphylline, a main pyrrolizidine alkaloid in Gynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis","volume":"40","author":"Wang","year":"2020","journal-title":"J. Appl. Toxicol."},{"key":"10.1016\/j.cbi.2026.112016_bib8","doi-asserted-by":"crossref","DOI":"10.1016\/j.foodchem.2022.132189","article-title":"Miniaturized and modified QuEChERS method with mesostructured silica as clean-up sorbent for pyrrolizidine alkaloids determination in aromatic herbs","volume":"380","author":"Izcara","year":"2022","journal-title":"Food Chem."},{"issue":"7","key":"10.1016\/j.cbi.2026.112016_bib9","article-title":"Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements","volume":"15","year":"2017","journal-title":"EFSA J."},{"key":"10.1016\/j.cbi.2026.112016_bib10","doi-asserted-by":"crossref","DOI":"10.1016\/j.fct.2023.113944","article-title":"Alternatives to animal testing in toxicity testing: current status and future perspectives in food safety assessments","volume":"179","author":"Reddy","year":"2023","journal-title":"Food Chem. Toxicol."},{"issue":"30","key":"10.1016\/j.cbi.2026.112016_bib11","doi-asserted-by":"crossref","first-page":"10974","DOI":"10.1021\/acs.est.3c01987","article-title":"Integrating in vitro data and physiologically based kinetic modeling to predict and compare acute neurotoxic doses of saxitoxin in rats, mice, and humans","volume":"57","author":"Chen","year":"2023","journal-title":"Environ. Sci. Technol."},{"issue":"29","key":"10.1016\/j.cbi.2026.112016_bib12","doi-asserted-by":"crossref","first-page":"16163","DOI":"10.1021\/acs.jafc.4c00969","article-title":"Physiologically based kinetic modeling-facilitated quantitative in vitro to in vivo extrapolation to predict the effects of aloe-emodin in rats and humans","volume":"72","author":"Ren","year":"2024","journal-title":"J. Agric. Food Chem."},{"issue":"6","key":"10.1016\/j.cbi.2026.112016_bib13","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1002\/mnfr.201000655","article-title":"Tutorial on physiologically based kinetic modeling in molecular nutrition and food research","volume":"55","author":"Rietjens","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"issue":"2","key":"10.1016\/j.cbi.2026.112016_bib14","article-title":"Protocol for primary mouse hepatocyte isolation","volume":"1","author":"Charni-Natan","year":"2020","journal-title":"STAR Protoc."},{"key":"10.1016\/j.cbi.2026.112016_bib15","doi-asserted-by":"crossref","DOI":"10.1016\/j.envpol.2023.122030","article-title":"Multiomics reveals new biomarkers and mechanistic insights into the combined toxicity effects of 2,2\u2032,4,4\u2032,5,5\u2032-hexachlorobiphenyl and atrazine exposures in MCF-7 cells","volume":"333","author":"Lu","year":"2023","journal-title":"Environ. Pollut."},{"issue":"13","key":"10.1016\/j.cbi.2026.112016_bib16","doi-asserted-by":"crossref","DOI":"10.1002\/mnfr.201801100","article-title":"Transcriptional response of white adipose tissue to withdrawal of vitamin B3","volume":"63","author":"Shi","year":"2019","journal-title":"Mol. Nutr. Food Res."},{"issue":"8","key":"10.1016\/j.cbi.2026.112016_bib17","doi-asserted-by":"crossref","DOI":"10.1002\/mnfr.201600878","article-title":"Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet","volume":"61","author":"Shi","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"10.1016\/j.cbi.2026.112016_bib18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.fct.2018.04.012","article-title":"Use of physiologically based kinetic modelling-facilitated reverse dosimetry to convert in vitro cytotoxicity data to predicted in vivo liver toxicity of lasiocarpine and riddelliine in rat","volume":"116","author":"Chen","year":"2018","journal-title":"Food Chem. Toxicol."},{"issue":"1","key":"10.1016\/j.cbi.2026.112016_bib19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0009-2797(85)80152-6","article-title":"In vivo covalent binding of retronecine-labelled [3H]seneciphylline and [3H]senecionine to DNA of rat liver, lung and kidney","volume":"54","author":"Candrian","year":"1985","journal-title":"Chem. Biol. Interact."},{"issue":"7","key":"10.1016\/j.cbi.2026.112016_bib20","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1093\/carcin\/15.7.1329","article-title":"In vivo metabolism of butadiene by mice and rats: a comparison of physiological model predictions and experimental data","volume":"15","author":"Medinsky","year":"1994","journal-title":"Carcinogenesis"},{"issue":"5","key":"10.1016\/j.cbi.2026.112016_bib21","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s11095-008-9823-9","article-title":"Relative importance of intestinal and hepatic glucuronidation-impact on the prediction of drug clearance","volume":"26","author":"Cubitt","year":"2009","journal-title":"Pharm. Res."},{"issue":"4","key":"10.1016\/j.cbi.2026.112016_bib22","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1177\/074823379701300401","article-title":"Physiological parameter values for physiologically based pharmacokinetic models","volume":"13","author":"Brown","year":"1997","journal-title":"Toxicol. Ind. Health"},{"issue":"1","key":"10.1016\/j.cbi.2026.112016_bib23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s002040050463","article-title":"A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans","volume":"72","author":"DeJongh","year":"1997","journal-title":"Arch. Toxicol."},{"issue":"9","key":"10.1016\/j.cbi.2026.112016_bib24","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.cbi.2026.112016_bib25","doi-asserted-by":"crossref","DOI":"10.1155\/2021\/8822304","article-title":"Toxic prediction of pyrrolizidine alkaloids and structure-dependent induction of apoptosis in HepaRG cells","volume":"2021","author":"Zheng","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"10.1016\/j.cbi.2026.112016_bib26","doi-asserted-by":"crossref","DOI":"10.1016\/j.exger.2023.112134","article-title":"Mitochondrial ROS production, oxidative stress and aging within and between species: evidences and recent advances on this aging effector","volume":"174","author":"Gomez","year":"2023","journal-title":"Exp. Gerontol."},{"key":"10.1016\/j.cbi.2026.112016_bib27","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.redox.2014.04.003","article-title":"Formation of electrophilic oxidation products from mitochondrial cardiolipin in vitro and in vivo in the context of apoptosis and atherosclerosis","volume":"2","author":"Zhong","year":"2014","journal-title":"Redox Biol."},{"key":"10.1016\/j.cbi.2026.112016_bib28","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1038\/onc.2009.46","article-title":"Noxa: at the tip of the balance between life and death","volume":"27","author":"Ploner","year":"2008","journal-title":"Oncogene"},{"issue":"10","key":"10.1016\/j.cbi.2026.112016_bib29","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1007\/s00018-010-0285-y","article-title":"Mitochondrial control of caspase-dependent and -independent cell death","volume":"67","author":"Pradelli","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"issue":"2","key":"10.1016\/j.cbi.2026.112016_bib30","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.celrep.2017.09.052","article-title":"Degradation of Bcl-2 by XIAP and ARTS promotes apoptosis","volume":"21","author":"Edison","year":"2017","journal-title":"Cell Rep."},{"issue":"1","key":"10.1016\/j.cbi.2026.112016_bib31","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/s41420-021-00563-4","article-title":"Septin4 promotes cardiomyocytes apoptosis by enhancing the VHL-mediated degradation of HIF-1\u03b1","volume":"7","author":"Wu","year":"2021","journal-title":"Cell Death Discov."},{"issue":"1","key":"10.1016\/j.cbi.2026.112016_bib32","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/cdd.2017.169","article-title":"How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?","volume":"25","author":"Aubrey","year":"2018","journal-title":"Cell Death Differ."},{"issue":"2","key":"10.1016\/j.cbi.2026.112016_bib33","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41419-021-03463-8","article-title":"p53 induces ARTS to promote mitochondrial apoptosis","volume":"12","author":"Hao","year":"2021","journal-title":"Cell Death Dis."},{"issue":"3","key":"10.1016\/j.cbi.2026.112016_bib34","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cell.2009.04.037","article-title":"Blinded by the light: the growing complexity of p53","volume":"137","author":"Vousden","year":"2009","journal-title":"Cell"},{"key":"10.1016\/j.cbi.2026.112016_bib35","series-title":"OECD Series on Testing and Assessment, No. 331, Environment, Health and Safety, Environment Directorate","article-title":"Guidance document on the characterisation, validation, and reporting of PBK models for regulatory purposes","year":"2021"},{"key":"10.1016\/j.cbi.2026.112016_bib36","series-title":"Characterization and Application of Physiologically Based Pharmacokinetic Models in Risk Assessment. Harmonization International Programme on Chemical Safety. WHO Guidance Document Project Document No. 9","year":"2010"},{"issue":"5","key":"10.1016\/j.cbi.2026.112016_bib37","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1007\/s00204-023-03453-z","article-title":"PBTK modeling of the pyrrolizidine alkaloid retrorsine to predict liver toxicity in mouse and rat","volume":"97","author":"Lehmann","year":"2023","journal-title":"Arch. Toxicol."},{"issue":"10","key":"10.1016\/j.cbi.2026.112016_bib38","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1007\/s00204-019-02563-x","article-title":"Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine","volume":"93","author":"Ning","year":"2019","journal-title":"Arch. Toxicol."},{"issue":"9","key":"10.1016\/j.cbi.2026.112016_bib39","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1007\/s00204-020-02798-z","article-title":"Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach","volume":"94","author":"Suparmi","year":"2020","journal-title":"Arch. Toxicol."},{"issue":"8","key":"10.1016\/j.cbi.2026.112016_bib40","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1007\/s00204-019-02515-5","article-title":"Prediction of in vivo genotoxicity of lasiocarpine and riddelliine in rat liver using a combined in vitro-physiologically based kinetic modelling-facilitated reverse dosimetry approach","volume":"93","author":"Chen","year":"2019","journal-title":"Arch. Toxicol."},{"issue":"3","key":"10.1016\/j.cbi.2026.112016_bib41","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1053\/j.gastro.2018.06.083","article-title":"Mitochondrial dysfunction and signaling in chronic liver diseases","volume":"155","author":"Mansouri","year":"2018","journal-title":"Gastroenterology"},{"issue":"6","key":"10.1016\/j.cbi.2026.112016_bib42","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1021\/tx0340302","article-title":"Gender differences in microsomal metabolic activation of hepatotoxic clivorine in rat","volume":"16","author":"Lin","year":"2003","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.cbi.2026.112016_bib43","doi-asserted-by":"crossref","DOI":"10.1016\/j.toxlet.2025.07.111","article-title":"S20-04 diversity in PBTK modelling and implications for regulatory application","volume":"411","author":"Steinbach","year":"2025","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.cbi.2026.112016_bib44","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.tiv.2017.11.016","article-title":"In vitro to in vivo extrapolation for high throughput prioritization and decision making","volume":"47","author":"Bell","year":"2018","journal-title":"Toxicol. Vitro"}],"container-title":["Chemico-Biological Interactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0009279726001249?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0009279726001249?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T01:35:17Z","timestamp":1776130517000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0009279726001249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":44,"alternative-id":["S0009279726001249"],"URL":"https:\/\/doi.org\/10.1016\/j.cbi.2026.112016","relation":{},"ISSN":["0009-2797"],"issn-type":[{"value":"0009-2797","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Seneciphylline induces hepatotoxicity through mitochondrial apoptosis: mechanistic elucidation and in vitro-to-in vivo prediction via physiologically based pharmacokinetic modeling-facilitated reverse dosimetry","name":"articletitle","label":"Article Title"},{"value":"Chemico-Biological Interactions","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.cbi.2026.112016","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"112016"}}