{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:08:47Z","timestamp":1789841327872,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1007622","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T00:00:00Z","timestamp":1591920000000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T00:00:00Z","timestamp":1591056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005347","name":"American Association for the Study of Liver Diseases","doi-asserted-by":"publisher","award":["Pinnacle Research Award"],"award-info":[{"award-number":["Pinnacle Research Award"]}],"id":[{"id":"10.13039\/100005347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK102142"],"award-info":[{"award-number":["DK102142"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1007622","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T13:43:05Z","timestamp":1591105385000},"page":"e1007622","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6848-0192","authenticated-orcid":true,"given":"Andrew K.","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6031-105X","authenticated-orcid":true,"given":"Glen E. P.","family":"Ropella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0401-0463","authenticated-orcid":true,"given":"Mitchell R.","family":"McGill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethi","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0219-8586","authenticated-orcid":true,"given":"Lopamudra","family":"Dutta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2146-4026","authenticated-orcid":true,"given":"Ryan C.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Jaeschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-6860","authenticated-orcid":true,"given":"C. Anthony","family":"Hunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"pcbi.1007622.ref001","first-page":"817","article-title":"The past and present of serum aminotransferases and the future of liver injury biomarkers","volume":"15","author":"MR McGill","year":"2016","journal-title":"EXCLI J"},{"issue":"9","key":"pcbi.1007622.ref002","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1080\/14737159.2018.1508998","article-title":"Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation","volume":"18","author":"MR McGill","year":"2018","journal-title":"Expert Rev Mol Diagn"},{"issue":"1","key":"pcbi.1007622.ref003","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1172\/JCI103055","article-title":"Transaminase activity in human blood","volume":"34","author":"A Karmen","year":"1995","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1007622.ref004","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1001\/jama.296.1.87","article-title":"Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial","volume":"296","author":"PB Watkins","year":"2006","journal-title":"JAMA"},{"issue":"9","key":"pcbi.1007622.ref005","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1101\/gr.090241.108","article-title":"Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans","volume":"19","author":"AH Harrill","year":"2009","journal-title":"Genome Res"},{"key":"pcbi.1007622.ref006","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1038\/psp.2013.74","article-title":"A mechanistic model of drug-induced liver injury AIDS the interpretation of elevated liver transaminase levels in a phase I clinical trial","volume":"3","author":"BA Howell","year":"2014","journal-title":"CPT Pharmacomet Syst Pharmacol"},{"issue":"3","key":"pcbi.1007622.ref007","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.taap.2013.03.026","article-title":"Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications","volume":"269","author":"MR McGill","year":"2013","journal-title":"Toxicol Appl Pharmacol"},{"issue":"12","key":"pcbi.1007622.ref008","doi-asserted-by":"crossref","first-page":"e1005253","DOI":"10.1371\/journal.pcbi.1005253","article-title":"Competing mechanistic hypotheses of acetaminophen-induced hepatotoxicity challenged by virtual experiments","volume":"12","author":"AK Smith","year":"2016","journal-title":"PLoS Comput Biol"},{"issue":"9","key":"pcbi.1007622.ref009","doi-asserted-by":"crossref","first-page":"e0198060","DOI":"10.1371\/journal.pone.0198060","article-title":"Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models","volume":"13","author":"X Fu","year":"2018","journal-title":"PLoS one"},{"issue":"11","key":"pcbi.1007622.ref010","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1007\/s11095-009-9958-3","article-title":"At the biological modeling and simulation frontier","volume":"26","author":"CA Hunt","year":"2009","journal-title":"Pharm Res"},{"issue":"1","key":"pcbi.1007622.ref011","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1124\/jpet.117.245019","article-title":"A model mechanism-based explanation of an in vitro-in vivo disconnect for improving extrapolation and translation","volume":"365","author":"AK Smith","year":"2018","journal-title":"J Pharmacol Exp Ther"},{"issue":"4","key":"pcbi.1007622.ref012","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/wsbm.1270","article-title":"Tuneable resolution as a systems biology approach for multi-scale, multi-compartment computational models","volume":"6","author":"DE Kirschner","year":"2014","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"pcbi.1007622.ref013","article-title":"Developing a vision for executing scientifically useful virtual biomedical experiments","author":"BK Petersen","year":"2016","journal-title":"Proceedings of the Agent-Directed Simulation Symposium"},{"key":"pcbi.1007622.ref014","unstructured":"Bartha P. Analogy and Analogical Reasoning. In: Zalta EN, editor. The Stanford Encyclopedia of Philosophy (Spring 2019 Edition). 2019. Available from: https:\/\/plato.stanford.edu\/archives\/spr2019\/entries\/reasoning-analogy\/"},{"issue":"5","key":"pcbi.1007622.ref015","doi-asserted-by":"crossref","first-page":"e0155855","DOI":"10.1371\/journal.pone.0155855","article-title":"Virtual experiments enable exploring and challenging explanatory mechanisms of immune-mediated P450 down-regulation","volume":"11","author":"BK Petersen","year":"2016","journal-title":"PloS One"},{"issue":"2","key":"pcbi.1007622.ref016","doi-asserted-by":"crossref","first-page":"e1000681","DOI":"10.1371\/journal.pcbi.1000681","article-title":"Identifying the rules of engagement enabling leukocyte rolling, activation, and adhesion","volume":"6","author":"J Tang","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1007622.ref017","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1742-4682-9-39","article-title":"Individualized, discrete event, simulations provide insight into inter- and intra-subject variability of extended-release, drug products","volume":"9","author":"SHJ Kim","year":"2012","journal-title":"Theor Biol Med Model"},{"issue":"1","key":"pcbi.1007622.ref018","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s13194-011-0038-2","article-title":"What is a mechanism? Thinking about mechanisms across the sciences","volume":"2","author":"PM Illari","year":"2012","journal-title":"Eur J Philos Sci"},{"issue":"5","key":"pcbi.1007622.ref019","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1086\/594538","article-title":"Thinking again about biological mechanisms","volume":"75","author":"L. Darden","year":"2008","journal-title":"Philos Sci"},{"issue":"1","key":"pcbi.1007622.ref020","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.biosystems.2006.02.004","article-title":"Formal agent-based modelling of intracellular chemical interactions","volume":"85","author":"M Pogson","year":"2006","journal-title":"Biosystems"},{"key":"pcbi.1007622.ref021","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/1742-4682-8-35","article-title":"Relational grounding facilitates development of scientifically useful multiscale models","volume":"8","author":"CA Hunt","year":"2011","journal-title":"Theor Biol Med Model"},{"key":"pcbi.1007622.ref022","unstructured":"Frigg R, Hartmann S. Models in Science. In: Zalta EN, editor. The Stanford Encyclopedia of Philosophy (Summer 2018 Edition). 2018. Available from: https:\/\/plato.stanford.edu\/archives\/sum2018\/entries\/models-science\/"},{"issue":"5","key":"pcbi.1007622.ref023","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1007\/s11095-007-9494-y","article-title":"Modeling and simulation of hepatic drug disposition using a physiologically based, multi-agent in silico liver","volume":"25","author":"L Yan","year":"2008","journal-title":"Pharm Res"},{"key":"pcbi.1007622.ref024","article-title":"Mechanistic agent-based damage and repair models as hypotheses for patterns of necrosis caused by drug induced liver injury","author":"AK Smith","year":"2014","journal-title":"SummerSim '14 Proceedings of the 2014 Summer Simulation Multiconference"},{"issue":"4","key":"pcbi.1007622.ref025","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1124\/dmd.107.019067","article-title":"Predictions of hepatic disposition properties using a mechanistically realistic, physiologically based model","volume":"36","author":"L Yan","year":"2008","journal-title":"Drug Metab Dispos"},{"issue":"2","key":"pcbi.1007622.ref026","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1124\/jpet.115.223537","article-title":"Cytochrome P450-independent mechanism of acetaminophen-induced injury in cultured mouse hepatocytes","volume":"354","author":"K Miyakawa","year":"2015","journal-title":"J Pharmacol Exp Ther"},{"issue":"3","key":"pcbi.1007622.ref027","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.jhep.2013.04.024","article-title":"CHOP is a critical regulator of acetaminophen-induced hepatotoxicity","volume":"59","author":"D Uzi","year":"2013","journal-title":"J Hepatol"},{"issue":"5","key":"pcbi.1007622.ref028","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3390\/pr6050056","article-title":"The spectrum of mechanism-oriented models and methods for explanations of biological phenomena","volume":"6","author":"CA Hunt","year":"2018","journal-title":"Processes"},{"issue":"3","key":"pcbi.1007622.ref029","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1057\/jos.2010.3","article-title":"Tutorial on agent-based modelling and simulation","volume":"4","author":"CM Macal","year":"2010","journal-title":"J Simul"},{"key":"pcbi.1007622.ref030","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/1752-0509-4-168","article-title":"Cloud computing and validation of expandable in silico livers","volume":"4","author":"GEP Ropella","year":"2010","journal-title":"BMC Syst Biol"},{"key":"pcbi.1007622.ref031","doi-asserted-by":"crossref","first-page":"37541","DOI":"10.1038\/srep37541","article-title":"Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver","volume":"7","author":"W Gamal","year":"2017","journal-title":"Sci Rep"},{"key":"pcbi.1007622.ref032","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.redox.2013.08.005","article-title":"Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver","volume":"1","author":"HM Ni","year":"2013","journal-title":"Redox Biol"},{"issue":"4","key":"pcbi.1007622.ref033","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s00228-012-1410-7","article-title":"Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations","volume":"69","author":"LP James","year":"2013","journal-title":"Eur J Clin Pharmacol"},{"key":"pcbi.1007622.ref034","first-page":"1","article-title":"1989 Toxic Hazards Research Unit Annual Report.","author":"RS Kutzman","year":"1990","journal-title":"Annual Report For The Period 1 October 1988\u201330 September 1989"},{"issue":"3","key":"pcbi.1007622.ref035","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1006\/taap.1999.8635","article-title":"Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice","volume":"156","author":"JA Lawson","year":"1999","journal-title":"Toxicol Appl Pharmacol"},{"issue":"1","key":"pcbi.1007622.ref036","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/toxsci\/kfi065","article-title":"Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice","volume":"84","author":"C Cover","year":"2005","journal-title":"Toxicol Sci"},{"issue":"3","key":"pcbi.1007622.ref037","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.taap.2012.08.015","article-title":"Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity","volume":"264","author":"MR McGill","year":"2012","journal-title":"Toxicol Appl Pharmacol"},{"issue":"1","key":"pcbi.1007622.ref038","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1093\/toxsci\/kfz029","article-title":"Propagation of pericentral necrosis during acetaminophen-induced liver injury: evidence for early interhepatocyte communication and information exchange","volume":"169","author":"RC Kennedy","year":"2019","journal-title":"Toxicol Sci"},{"key":"pcbi.1007622.ref039","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-94-007-7675-3_5","volume-title":"Biomarkers in Liver Disease","author":"MR McGill","year":"2017"},{"issue":"9","key":"pcbi.1007622.ref040","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1139\/y89-160","article-title":"Hepatic zonation of drug metabolizing enzymes. Studies on hepatocytes isolated from the periportal or perivenous region of the liver acinus","volume":"67","author":"M Gascon-Barr\u00e9","year":"1989","journal-title":"Can J Physiol Pharmacol"},{"issue":"7641","key":"pcbi.1007622.ref041","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nature21065","article-title":"Single-cell spatial reconstruction reveals global division of labour in the mammalian liver","volume":"542","author":"KB Halpern","year":"2017","journal-title":"Nature"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1007622","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T00:00:00Z","timestamp":1591920000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1007622","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T13:43:46Z","timestamp":1591969426000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1007622"}},"subtitle":[],"editor":[{"given":"Anders","family":"Wallqvist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,6,2]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1007622","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2019.12.24.887869","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,2]]}}}