{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T01:29:18Z","timestamp":1782523758225,"version":"3.54.5"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medicines Initiative 2","award":["116030"],"award-info":[{"award-number":["116030"]}]},{"name":"European Union\u2019s Horizon 2020"},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centre for Drug Safety Science","award":["MR\/L006758\/1"],"award-info":[{"award-number":["MR\/L006758\/1"]}]},{"name":"Senior Non-clinical","award":["MR\/X007413\/1"],"award-info":[{"award-number":["MR\/X007413\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical species and humans. Species differences in sensitivity to acetaminophen (APAP) liver injury have been related to differences in the fraction of the drug that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically based pharmacokinetic modeling to identify oral doses of APAP (300 and 1000\u2009mg\/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats, indicative of a more robust transcriptional adaptation to the equivalent insult. Components of these pathways were also found to be expressed at a higher basal level in the livers of rats compared with both mice and humans. Our findings exemplify a systems approach to understanding differential species sensitivity to hepatotoxicity. Multiomics analysis indicated that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans, with important implications for species selection and human translation in the safety testing of new drug candidates associated with reactive metabolite formation.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad085","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:30:04Z","timestamp":1693297804000},"page":"112-125","source":"Crossref","is-referenced-by-count":18,"title":["A systems approach reveals species differences in hepatic stress response capacity"],"prefix":"10.1093","volume":"196","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3378-5524","authenticated-orcid":false,"given":"Giusy","family":"Russomanno","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowena","family":"Sison-Young","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia A","family":"Livoti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Coghlan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-1136","authenticated-orcid":false,"given":"Rosalind E","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"},{"name":"CDSS Bioanalytical Facility, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9549-1719","authenticated-orcid":false,"given":"Steven J","family":"Kunnen","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University , Leiden, 2311 EZ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciar\u00e1n P","family":"Fisher","sequence":"additional","affiliation":[{"name":"Simcyp Division, Certara UK , Sheffield, S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Reddyhoff","sequence":"additional","affiliation":[{"name":"Simcyp Division, Certara UK , Sheffield, S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain","family":"Gardner","sequence":"additional","affiliation":[{"name":"Simcyp Division, Certara UK , Sheffield, S1 2BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeeb H","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"},{"name":"Department of Hepatobiliary Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust , Liverpool, L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W","family":"Fenwick","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust , Liverpool, L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Systems Biology, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Vermeil De Conchard","sequence":"additional","affiliation":[{"name":"Translational Medicine, Non Clinical Safety, Biologie Servier , Gidy, 45520, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Simonin","sequence":"additional","affiliation":[{"name":"Translational Medicine, Non Clinical Safety, Biologie Servier , Gidy, 45520, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Bertheux","sequence":"additional","affiliation":[{"name":"Translational Medicine, Non Clinical Safety, Biologie Servier , Gidy, 45520, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J","family":"Weaver","sequence":"additional","affiliation":[{"name":"Institut de R&D Servier Paris-Saclay , Gif sur Yvette, 91190, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L","family":"Johnson","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company , Indianapolis, Indiana 46225, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Liguori","sequence":"additional","affiliation":[{"name":"AbbVie Inc., Pre-Clinical Safety , Chicago, Illinois 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Clausznitzer","sequence":"additional","affiliation":[{"name":"AbbVie Deutschland GmbH & Co. KG, DMPK-BA , Ludwigshafen, 67061, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L","family":"Stevens","sequence":"additional","affiliation":[{"name":"Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University , Leiden, 2311 EZ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E","family":"Goldring","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M","family":"Copple","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool , Liverpool, L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"2023103009451021300_kfad085-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/026119291003801S01","article-title":"Mind the gap","volume":"38(Suppl. 1)","author":"Aithal","year":"2010","journal-title":"Altern. Lab. Anim"},{"key":"2023103009451021300_kfad085-B2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet"},{"key":"2023103009451021300_kfad085-B3","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0140-6736(10)60274-7","article-title":"Acute liver failure","volume":"376","author":"Bernal","year":"2010","journal-title":"Lancet"},{"key":"2023103009451021300_kfad085-B4","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/0278-6915(86)90172-9","article-title":"Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol","volume":"24","author":"Boobis","year":"1986","journal-title":"Food Chem. Toxicol"},{"key":"2023103009451021300_kfad085-B5","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41586-019-1338-5","article-title":"Gene expression across mammalian organ development","volume":"571","author":"Cardoso-Moreira","year":"2019","journal-title":"Nature"},{"key":"2023103009451021300_kfad085-B6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jfda.2014.03.007","article-title":"Autophagy in drug-induced liver toxicity","volume":"22","author":"Chen","year":"2014","journal-title":"J. Food Drug Anal"},{"key":"2023103009451021300_kfad085-B7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3390\/cells7120278","article-title":"Autophagy: An essential degradation program for cellular homeostasis and life","volume":"7","author":"Chun","year":"2018","journal-title":"Cells"},{"key":"2023103009451021300_kfad085-B8","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cotox.2016.10.004","article-title":"Roles of Nrf2 in drug and chemical toxicity","volume":"1","author":"Clarke","year":"2016","journal-title":"Curr. Opin. Toxicol"},{"key":"2023103009451021300_kfad085-B9","doi-asserted-by":"crossref","first-page":"16782","DOI":"10.1074\/jbc.M109.096545","article-title":"Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway","volume":"285","author":"Copple","year":"2010","journal-title":"J. Biol. Chem"},{"key":"2023103009451021300_kfad085-B10","first-page":"54","article-title":"Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by n-acetyl-L-cysteine in vivo: Studies with n-acetyl-D-cysteine in mice","volume":"238","author":"Corcoran","year":"1986","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"2023103009451021300_kfad085-B11","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","article-title":"DIA-NN: Neural networks and interference correction enable deep proteome coverage in high throughput","volume":"17","author":"Demichev","year":"2020","journal-title":"Nat. Methods"},{"key":"2023103009451021300_kfad085-B12","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene expression omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"2023103009451021300_kfad085-B13","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nrd1329","article-title":"First dose of potential new medicines to humans: How animals help","volume":"3","author":"Greaves","year":"2004","journal-title":"Nat. Rev. Drug Discov"},{"key":"2023103009451021300_kfad085-B14","first-page":"91","article-title":"Species variation in toxication and detoxication of acetaminophen in vivo: A comparative study of biliary and urinary excretion of acetaminophen metabolites","volume":"244","author":"Gregus","year":"1988","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"2023103009451021300_kfad085-B15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/j.gastro.2006.03.045","article-title":"c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity","volume":"131","author":"Gunawan","year":"2006","journal-title":"Gastroenterology"},{"key":"2023103009451021300_kfad085-B16","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":"Harrill","year":"2009","journal-title":"Genome Res"},{"key":"2023103009451021300_kfad085-B17","doi-asserted-by":"crossref","first-page":"12741","DOI":"10.1073\/pnas.220176997","article-title":"Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi","volume":"97","author":"Henderson","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2023103009451021300_kfad085-B18","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/sj.mn.7800204","article-title":"Early hepatic microvascular injury in response to acetaminophen toxicity","volume":"10","author":"Ito","year":"2003","journal-title":"Microcirculation"},{"key":"2023103009451021300_kfad085-B19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12011-017-1219-4","article-title":"Effect of arsenic exposure on Nrf2-Keap1 pathway and epigenetic modification","volume":"185","author":"Janasik","year":"2018","journal-title":"Biol. Trace Elem. Res"},{"key":"2023103009451021300_kfad085-B20","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.freeradbiomed.2015.06.014","article-title":"P62 links autophagy and Nrf2 signaling","volume":"88","author":"Jiang","year":"2015","journal-title":"Free Radic. Biol. Med"},{"key":"2023103009451021300_kfad085-B21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/toxsci\/kfaa094","article-title":"Development and application of a transcriptomic signature of bioactivation in an advanced in vitro liver model to reduce drug-induced liver injury risk early in the pharmaceutical pipeline","volume":"177","author":"Kang","year":"2020","journal-title":"Toxicol. Sci"},{"key":"2023103009451021300_kfad085-B22","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/hep.20948","article-title":"Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study","volume":"42","author":"Larson","year":"2005","journal-title":"Hepatology"},{"key":"2023103009451021300_kfad085-B23","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/jbt.21463","article-title":"Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway","volume":"27","author":"Lau","year":"2013","journal-title":"J. Biochem. Mol. Toxicol"},{"key":"2023103009451021300_kfad085-B24","doi-asserted-by":"crossref","first-page":"16700","DOI":"10.1074\/jbc.M513825200","article-title":"Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): Implications for interspecies differences in mitochondrial toxicity of fialuridine","volume":"281","author":"Lee","year":"2006","journal-title":"J. Biol. Chem"},{"key":"2023103009451021300_kfad085-B25","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1124\/jpet.106.119073","article-title":"Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP\/SLC10A1) by bosentan: A mechanism for species differences in hepatotoxicity","volume":"321","author":"Leslie","year":"2007","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"2023103009451021300_kfad085-B26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1124\/dmd.120.000181","article-title":"Sex-, age-, and race\/ethnicity-dependent variations in drug-processing and Nrf2-regulated genes in human livers","volume":"49","author":"Liu","year":"2021","journal-title":"Drug Metab. Dispos"},{"key":"2023103009451021300_kfad085-B27","first-page":"D407","article-title":"Biomodels-15 years of sharing computational models in life science","volume":"48","author":"Malik-Sheriff","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2023103009451021300_kfad085-B28","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":"McGill","year":"2012","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2023103009451021300_kfad085-B29","doi-asserted-by":"crossref","first-page":"e0128429","DOI":"10.1371\/journal.pone.0128429","article-title":"Laboratory rodent diets contain toxic levels of environmental contaminants: Implications for regulatory tests","volume":"10","author":"Mesnage","year":"2015","journal-title":"PLoS One"},{"key":"2023103009451021300_kfad085-B30","doi-asserted-by":"crossref","first-page":"542","DOI":"10.4161\/auto.4600","article-title":"How to interpret LC3 immunoblotting","volume":"3","author":"Mizushima","year":"2007","journal-title":"Autophagy"},{"key":"2023103009451021300_kfad085-B31","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/toxsci\/kfaa088","article-title":"Application of a rat liver drug bioactivation transcriptional response assay early in drug development that informs chemically reactive metabolite formation and potential for drug-induced liver injury","volume":"177","author":"Monroe","year":"2020","journal-title":"Toxicol. Sci"},{"key":"2023103009451021300_kfad085-B32","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.taap.2017.09.006","article-title":"Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database","volume":"334","author":"Monticello","year":"2017","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2023103009451021300_kfad085-B33","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/hep.24690","article-title":"Activation of autophagy protects against acetaminophen-induced hepatotoxicity","volume":"55","author":"Ni","year":"2012","journal-title":"Hepatology"},{"key":"2023103009451021300_kfad085-B34","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jhep.2016.04.025","article-title":"Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice","volume":"65","author":"Ni","year":"2016","journal-title":"J. Hepatol"},{"key":"2023103009451021300_kfad085-B35","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1006\/rtph.2000.1399","article-title":"Concordance of the toxicity of pharmaceuticals in humans and in animals","volume":"32","author":"Olson","year":"2000","journal-title":"Regul. Toxicol. Pharmacol"},{"key":"2023103009451021300_kfad085-B36","doi-asserted-by":"crossref","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol"},{"key":"2023103009451021300_kfad085-B37","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The pride database and related tools and resources in 2019: Improving support for quantification data","volume":"47","author":"Perez-Riverol","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023103009451021300_kfad085-B38","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":"2023103009451021300_kfad085-B39","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023103009451021300_kfad085-B40","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.taap.2010.04.015","article-title":"c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity","volume":"246","author":"Saito","year":"2010","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2023103009451021300_kfad085-B41","doi-asserted-by":"crossref","first-page":"96476","DOI":"10.18632\/oncotarget.22255","article-title":"Diurnal liver mass is associated with ribosome biogenesis","volume":"8","author":"Sinturel","year":"2017","journal-title":"Oncotarget"},{"key":"2023103009451021300_kfad085-B42","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1021\/tx034033e","article-title":"Mechanisms of troglitazone hepatotoxicity","volume":"16","author":"Smith","year":"2003","journal-title":"Chem. Res. Toxicol"},{"key":"2023103009451021300_kfad085-B43","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/tpj.2017.17","article-title":"Toxicogenomic module associations with pathogenesis: A network-based approach to understanding drug toxicity","volume":"18","author":"Sutherland","year":"2018","journal-title":"Pharmacogenomics J"},{"key":"2023103009451021300_kfad085-B44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1006\/faat.1996.0038","article-title":"Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: Role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding","volume":"30","author":"Tarloff","year":"1996","journal-title":"Fundam. Appl. Toxicol"},{"key":"2023103009451021300_kfad085-B45","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/0006-2952(87)90412-6","article-title":"Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite","volume":"36","author":"Tee","year":"1987","journal-title":"Biochem. Pharmacol"},{"key":"2023103009451021300_kfad085-B46","doi-asserted-by":"crossref","first-page":"e1010174","DOI":"10.1371\/journal.pcbi.1010174","article-title":"Integrated view and comparative analysis of baseline protein expression in mouse and rat tissues","volume":"18","author":"Wang","year":"2022","journal-title":"PLoS Comput. Biol"},{"key":"2023103009451021300_kfad085-B47","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41573-019-0048-x","article-title":"Managing the challenge of drug-induced liver injury: A roadmap for the development and deployment of preclinical predictive models","volume":"19","author":"Weaver","year":"2020","journal-title":"Nat. Rev. Drug Discov"},{"key":"2023103009451021300_kfad085-B48","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/nrd2423","article-title":"Identifying genetic risk factors for serious adverse drug reactions: Current progress and challenges","volume":"6","author":"Wilke","year":"2007","journal-title":"Nat. Rev. Drug Discov"},{"key":"2023103009451021300_kfad085-B49","doi-asserted-by":"crossref","first-page":"647084","DOI":"10.3389\/fphar.2021.647084","article-title":"Research on the species difference of the hepatotoxicity of medicine based on transcriptome","volume":"12","author":"Xu","year":"2021","journal-title":"Front. Pharmacol"},{"key":"2023103009451021300_kfad085-B50","first-page":"131","article-title":"Acetaminophen-induced hepatotoxicity: A comprehensive update","volume":"4","author":"Yoon","year":"2016","journal-title":"J. Clin. Transl. Hepatol"},{"key":"2023103009451021300_kfad085-B51","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2023103009451021300_kfad085-B52","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1074\/mcp.TIR119.001646","article-title":"DEqMS: A method for accurate variance estimation in differential protein expression analysis","volume":"19","author":"Zhu","year":"2020","journal-title":"Mol. Cell. Proteomics"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfad085\/51773036\/kfad085.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/196\/1\/112\/52638432\/kfad085.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/196\/1\/112\/52638432\/kfad085.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T05:46:43Z","timestamp":1698644803000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/196\/1\/112\/7255943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,30]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,8,30]]},"published-print":{"date-parts":[[2023,10,30]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfad085","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.04.13.488145","asserted-by":"object"}]},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,11,1]]},"published":{"date-parts":[[2023,8,30]]}}}