{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:41:42Z","timestamp":1791686502634,"version":"4.3.4"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T00:00:00Z","timestamp":1683158400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T00:00:00Z","timestamp":1683158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Biol Toxicol"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cell-based metabolomics provides multiparametric physiologically relevant readouts that can be highly advantageous for improved, biologically based decision making in early stages of compound development. Here, we present the development of a 96-well plate\n                    <jats:italic>LC<\/jats:italic>\n                    -\n                    <jats:italic>MS<\/jats:italic>\n                    \/\n                    <jats:italic>MS-<\/jats:italic>\n                    based targeted metabolomics screening platform for the classification of liver toxicity modes of action (MoAs) in HepG2 cells. Different parameters of the workflow (cell seeding density, passage number, cytotoxicity testing, sample preparation, metabolite extraction, analytical method, and data processing) were optimized and standardized to increase the efficiency of the testing platform. The applicability of the system was tested with seven substances known to be representative of three different liver toxicity MoAs (peroxisome proliferation, liver enzyme induction, and liver enzyme inhibition). Five concentrations per substance, aimed at covering the complete dose-response curve, were analyzed and 221 uniquely identified metabolites were measured, annotated, and allocated in 12 different metabolite classes such as amino acids, carbohydrates, energy metabolism, nucleobases, vitamins and cofactors, and diverse lipid classes. Multivariate and univariate analyses showed a dose response of the metabolic effects, a clear differentiation between liver toxicity MoAs and resulted in the identification of metabolite patterns specific for each MoA. Key metabolites indicative of both general and mechanistic specific hepatotoxicity were identified. The method presented here offers a multiparametric, mechanistic-based, and cost-effective hepatotoxicity screening that provides MoA classification and sheds light into the pathways involved in the toxicological mechanism. This assay can be implemented as a reliable compound screening platform for improved safety assessment in early compound development pipelines.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10565-023-09809-6","type":"journal-article","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T23:28:26Z","timestamp":1683156506000},"page":"2899-2917","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A high-throughput metabolomics in vitro platform for the characterization of hepatotoxicity"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8795-7061","authenticated-orcid":false,"given":"Sabina","family":"Ramirez-Hincapie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-8527","authenticated-orcid":false,"given":"Barbara","family":"Birk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0886-5474","authenticated-orcid":false,"given":"Philipp","family":"Ternes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6055-6324","authenticated-orcid":false,"given":"Varun","family":"Giri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7124-6727","authenticated-orcid":false,"given":"Volker","family":"Haake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7733-0196","authenticated-orcid":false,"given":"Michael","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4269-1316","authenticated-orcid":false,"given":"Franziska Maria","family":"Zickgraf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3337-444X","authenticated-orcid":false,"given":"Andreas","family":"Verlohner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-0035","authenticated-orcid":false,"given":"Hans-Albrecht","family":"Huener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1316-8756","authenticated-orcid":false,"given":"Hennicke","family":"Kamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5650-5380","authenticated-orcid":false,"given":"Peter","family":"Driemert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3756-1904","authenticated-orcid":false,"given":"Robert","family":"Landsiedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-8032","authenticated-orcid":false,"given":"Elke","family":"Richling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothee","family":"Funk-Weyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4264-9217","authenticated-orcid":false,"given":"Bennard","family":"van Ravenzwaay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,4]]},"reference":[{"key":"9809_CR1","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1093\/toxsci\/kfn255","volume":"1072","author":"ME Andersen","year":"2009","unstructured":"Andersen ME, Krewski D. Toxicity testing in the 21st century: bringing the vision to life. Toxicol Sci. 2009;1072:324\u201330.","journal-title":"Toxicol Sci."},{"key":"9809_CR2","doi-asserted-by":"publisher","first-page":"826","DOI":"10.3389\/fmolb.2022.932261","volume":"9","author":"C Andresen","year":"2022","unstructured":"Andresen C, Boch T, Gegner HM, Mechtel N, Narr A, Birgin E, Rasbach E, Rahbari N, Trumpp A, Poschet G. Comparison of extraction methods for intracellular metabolomics of human tissues. Front Mol Biosci. 2022;9:826.","journal-title":"Front Mol Biosci."},{"key":"9809_CR3","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/s41589-022-00970-3","volume":"185","author":"M Anglada-Girotto","year":"2022","unstructured":"Anglada-Girotto M, Handschin G, Ortmayr K, Campos AI, Gillet L, Manfredi P, Mulholland CV, Berney M, Jenal U, Picotti P, Zampieri M. Combining CRISPRi and metabolomics for functional annotation of compound libraries. Nat Chem Biol. 2022;185:482\u201391.","journal-title":"Nat Chem Biol."},{"key":"9809_CR4","doi-asserted-by":"publisher","first-page":"5678","DOI":"10.1074\/jbc.273.10.5678","volume":"27310","author":"T Aoyama","year":"1998","unstructured":"Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1). J Biol Chem. 1998;27310:5678\u201384.","journal-title":"J Biol Chem."},{"key":"9809_CR5","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.toxlet.2011.03.013","volume":"2033","author":"G Balcke","year":"2011","unstructured":"Balcke G, Kolle S, Kamp H, Bethan B, Looser R, Wagner S, Landsiedel R, Van Ravenzwaay B. Linking energy metabolism to dysfunctions in mitochondrial respiration\u2013a metabolomics in vitro approach. Toxicol Lett. 2011;2033:200\u20139.","journal-title":"Toxicol Lett."},{"key":"9809_CR6","first-page":"12","volume":"161","author":"R Barcelos","year":"2016","unstructured":"Barcelos R, Stefanello S, Mauriz J, Gonzalez-Gallego J, Soares F. Creatine and the liver: metabolism and possible interactions. Mini Rev Med Chem. 2016;161:12\u20138.","journal-title":"Mini Rev Med Chem."},{"key":"9809_CR7","doi-asserted-by":"crossref","unstructured":"Bevilacqua A, Bizzarri M. Inositols in insulin signaling and glucose metabolism. Int. J. Endocrinol. 2018;2018","DOI":"10.1155\/2018\/1968450"},{"key":"9809_CR8","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.jhep.2013.05.030","volume":"594","author":"D Beyoglu","year":"2013","unstructured":"Beyoglu D, Idle JR. The metabolomic window into hepatobiliary disease. J Hepatol. 2013;594:842\u201358.","journal-title":"J Hepatol."},{"key":"9809_CR9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.toxlet.2021.09.011","volume":"353","author":"B Birk","year":"2021","unstructured":"Birk B, Haake V, Sperber S, Herold M, Wallisch SK, Huener H-A, Verlohner A, Amma MM, Walk T, Hernandez TR. Use of in vitro metabolomics in NRK cells to help predicting nephrotoxicity and differentiating the MoA of nephrotoxicants. Toxicol Lett. 2021;353:43\u201359.","journal-title":"Toxicol Lett."},{"key":"9809_CR10","first-page":"2153","volume":"6164","author":"N Bordag","year":"2016","unstructured":"Bordag N, Rennfahrt U, Nachtigall J, Maldonado S, Reszka R, Ramirez-Hernandez T, Kamp H, Fux E, Van Ravenzwaay B. Fast sampling of adherent cell cultures for optimal metabolomics results. Metabolomics. 2016;6164:2153. 0769.1000164","journal-title":"Metabolomics."},{"key":"9809_CR11","first-page":"1","volume":"291","author":"SE Crawford","year":"2017","unstructured":"Crawford SE, Hartung T, Hollert H, Mathes B, van Ravenzwaay B, Steger-Hartmann T, Studer C, Krug HF. Green toxicology: a strategy for sustainable chemical and material development. Environ Sci Eur. 2017;291:1\u201316.","journal-title":"Environ Sci Eur."},{"key":"9809_CR12","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1093\/toxsci\/kfab036","volume":"1812","author":"DM Crizer","year":"2021","unstructured":"Crizer DM, Ramaiahgari SC, Ferguson SS, Rice JR, Dunlap PE, Sipes NS, Auerbach SS, Merrick BA, DeVito MJ. Benchmark concentrations for untargeted metabolomics versus transcriptomics for liver injury compounds in in vitro liver models. Toxicol Sci. 2021;1812:175\u201386.","journal-title":"Toxicol Sci."},{"key":"9809_CR13","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.toxlet.2017.12.015","volume":"286","author":"M Cuykx","year":"2018","unstructured":"Cuykx M, Claes L, Rodrigues RM, Vanhaecke T, Covaci A. Metabolomics profiling of steatosis progression in HepaRG\u00ae cells using sodium valproate. Toxicol Lett. 2018a;286:22\u201330.","journal-title":"Toxicol Lett."},{"key":"9809_CR14","doi-asserted-by":"publisher","first-page":"3007","DOI":"10.1007\/s00204-018-2286-9","volume":"9210","author":"M Cuykx","year":"2018","unstructured":"Cuykx M, Rodrigues RM, Laukens K, Vanhaecke T, Covaci A. In vitro assessment of hepatotoxicity by metabolomics: a review. Arch Toxicol. 2018b;9210:3007\u201329.","journal-title":"Arch Toxicol."},{"key":"9809_CR15","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1093\/toxsci\/kfl103","volume":"951","author":"DJ Dix","year":"2007","unstructured":"Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci. 2007;951:5\u201312.","journal-title":"Toxicol Sci."},{"key":"9809_CR16","first-page":"1","volume":"11","author":"S Dubuis","year":"2018","unstructured":"Dubuis S, Ortmayr K, Zampieri M. A framework for large-scale metabolome drug profiling links coenzyme A metabolism to the toxicity of anti-cancer drug dichloroacetate. Commun Biol. 2018;11:1\u201311.","journal-title":"Commun Biol."},{"key":"9809_CR17","first-page":"1","volume":"61","author":"JC Garc\u00eda-Ca\u00f1averas","year":"2016","unstructured":"Garc\u00eda-Ca\u00f1averas JC, Castell JV, Donato MT, Lahoz A. A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury. Sci Rep. 2016;61:1\u201312.","journal-title":"Sci Rep."},{"key":"9809_CR18","doi-asserted-by":"publisher","first-page":"4825","DOI":"10.1021\/pr200629p","volume":"1010","author":"JC Garc\u00eda-Canaveras","year":"2011","unstructured":"Garc\u00eda-Canaveras JC, Donato MT, Castell JV, Lahoz A. A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations. J Proteome Res. 2011;1010:4825\u201334.","journal-title":"J Proteome Res."},{"key":"9809_CR19","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1007\/s00204-022-03348-5","volume":"9611","author":"A Gerdemann","year":"2022","unstructured":"Gerdemann A, Behrens M, Esselen M, Humpf H-U. Metabolic profiling as a powerful tool for the analysis of cellular alterations caused by 20 mycotoxins in HepG2 cells. Arch. Toxicol. 2022;9611:2983\u201398.","journal-title":"Arch. Toxicol."},{"key":"9809_CR20","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nbt.4101","volume":"364","author":"C Guijas","year":"2018","unstructured":"Guijas C, Montenegro-Burke JR, Warth B, Spilker ME, Siuzdak G. Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat Biotechnol. 2018;364:316\u201320.","journal-title":"Nat Biotechnol."},{"key":"9809_CR21","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1093\/toxsci\/kfx029","volume":"1571","author":"P Haegler","year":"2017","unstructured":"Haegler P, Joerin L, Kr\u00e4henb\u00fchl S, Bouitbir J. Hepatocellular toxicity of imidazole and triazole antimycotic agents. Toxicol Sci. 2017;1571:183\u201395.","journal-title":"Toxicol Sci"},{"key":"9809_CR22","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/nmeth.3853","volume":"136","author":"M Hafner","year":"2016","unstructured":"Hafner M, Niepel M, Chung M, Sorger PK. Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Methods. 2016;136:521\u20137.","journal-title":"Nat Methods."},{"key":"9809_CR23","doi-asserted-by":"publisher","first-page":"e0248942","DOI":"10.1371\/journal.pone.0248942","volume":"163","author":"J-W Huang","year":"2021","unstructured":"Huang J-W, Kuo C-H, Kuo H-C, Shih J-Y, Tsai T-W, Chang L-C. Cell metabolomics analyses revealed a role of altered fatty acid oxidation in neurotoxicity pattern difference between nab-paclitaxel and solvent-based paclitaxel. PloS One. 2021;163:e0248942.","journal-title":"PloS One."},{"key":"9809_CR24","first-page":"C1073","volume":"2834","author":"MJ Hunt","year":"2002","unstructured":"Hunt MJ, Tyagi SC. Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation. Am J Phys Cell Phys. 2002;2834:C1073\u20139.","journal-title":"Am J Phys Cell Phys."},{"key":"9809_CR25","doi-asserted-by":"publisher","first-page":"462222","DOI":"10.1016\/j.chroma.2021.462222","volume":"1649","author":"BK Jeon","year":"2021","unstructured":"Jeon BK, Jang Y, Lee EM, Moon JH, Lee HJ, Lee DY. A systematic approach to metabolic characterization of thyroid-disrupting chemicals and their in vitro biotransformants based on prediction-assisted metabolomic analysis. J Chromatogr A. 2021;1649:462222.","journal-title":"J Chromatogr A."},{"key":"9809_CR26","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.4155\/bio.12.214","volume":"418","author":"H Kamp","year":"2012","unstructured":"Kamp H, Fabian E, Groeters S, Herold M, Krennrich G, Looser R, Mattes W, Mellert W, Prokoudine A, Ruiz-Noppinger P. Application of in vivo metabolomics to preclinical\/toxicological studies: case study on phenytoin-induced systemic toxicity. Bioanalysis. 2012;418:2291\u2013301.","journal-title":"Bioanalysis."},{"key":"9809_CR27","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1093\/toxsci\/kfaa094","volume":"1771","author":"W Kang","year":"2020","unstructured":"Kang W, Podtelezhnikov AA, Tanis KQ, Pacchione S, Su M, Bleicher KB, Wang Z, Laws GM, Griffiths TG, Kuhls MC. 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. Toxicol Sci. 2020;1771:121\u201339.","journal-title":"Toxicol Sci."},{"key":"9809_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00204-019-02613-4","volume":"941","author":"D Krewski","year":"2020","unstructured":"Krewski D, Andersen ME, Tyshenko MG, Krishnan K, Hartung T, Boekelheide K, Wambaugh JF, Jones D, Whelan M, Thomas R. Toxicity testing in the 21st century: progress in the past decade and future perspectives. Arch Toxicol. 2020;941:1\u201358.","journal-title":"Arch Toxicol."},{"key":"9809_CR29","doi-asserted-by":"publisher","first-page":"3739","DOI":"10.1038\/ncomms4739","volume":"5","author":"SJ Kwon","year":"2014","unstructured":"Kwon SJ, Lee DW, Shah DA, Ku B, Jeon SY, Solanki K, Ryan JD, Clark DS, Dordick JS, Lee MY. High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening. Nat Commun. 2014;5:3739.","journal-title":"Nat Commun."},{"key":"9809_CR30","doi-asserted-by":"publisher","first-page":"5798","DOI":"10.1038\/s41598-020-62848-5","volume":"101","author":"P Larsson","year":"2020","unstructured":"Larsson P, Engqvist H, Biermann J, Werner Ronnerman E, Forssell-Aronsson E, Kovacs A, Karlsson P, Helou K, Parris TZ. Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens. Sci Rep. 2020;101:5798.","journal-title":"Sci Rep."},{"key":"9809_CR31","doi-asserted-by":"crossref","unstructured":"Leonardi R, Jackowski S. Biosynthesis of pantothenic acid and coenzyme A. EcoSal Plus. 2007;22","DOI":"10.1128\/ecosal.3.6.3.4"},{"key":"9809_CR32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11306-021-01867-3","volume":"181","author":"JM Malinowska","year":"2022","unstructured":"Malinowska JM, Palosaari T, Sund J, Carpi D, Bouhifd M, Weber RJM, Whelan M, Viant MR. Integrating in vitro metabolomics with a 96-well high-throughput screening platform. Metabolomics. 2022;181:11.","journal-title":"Metabolomics."},{"key":"9809_CR33","first-page":"207","volume":"284","author":"MR Mas","year":"2004","unstructured":"Mas MR, Comert B, Oncu K, Vural SA, Akay C, Tasci I, Ozkomur E, Serdar M, Mas N, Alcigir G. The effect of taurine treatment on oxidative stress in experimental liver fibrosis. Hepatol Res. 2004;284:207\u201315.","journal-title":"Hepatol Res."},{"key":"9809_CR34","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/j.toxlet.2014.07.021","volume":"2303","author":"W Mattes","year":"2014","unstructured":"Mattes W, Davis K, Fabian E, Greenhaw J, Herold M, Looser R, Mellert W, Groeters S, Marxfeld H, Moeller N, Montoya-Parra G, Prokoudine A, van Ravenzwaay B, Strauss V, Walk T, Kamp H. Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma. Toxicol Lett. 2014;2303:467\u201378.","journal-title":"Toxicol Lett."},{"key":"9809_CR35","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.3390\/ijms23063315","volume":"236","author":"M Mihajlovic","year":"2022","unstructured":"Mihajlovic M, Vinken M. Mitochondria as the target of hepatotoxicity and drug-induced liver injury: molecular mechanisms and detection methods. Int J Mol Sci. 2022;236:3315.","journal-title":"Int J Mol Sci."},{"key":"9809_CR36","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1080\/03602532.2022.2064487","volume":"542","author":"M Mirahmad","year":"2022","unstructured":"Mirahmad M, Sabourian R, Mahdavi M, Larijani B, Safavi M. In vitro cell-based models of drug-induced hepatotoxicity screening: progress and limitation. Drug Metab Rev. 2022;542:161\u201393.","journal-title":"Drug Metab Rev."},{"key":"9809_CR37","doi-asserted-by":"publisher","first-page":"22119","DOI":"10.1038\/s41598-021-01652-1","volume":"111","author":"M Moreno-Torres","year":"2021","unstructured":"Moreno-Torres M, Garcia-Llorens G, Moro E, Mendez R, Quintas G, Castell JV. Factors that influence the quality of metabolomics data in in vitro cell toxicity studies: a systematic survey. Sci Rep. 2021;111:22119.","journal-title":"Sci Rep."},{"key":"9809_CR38","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1007\/s00726-018-2605-8","volume":"509","author":"S Murakami","year":"2018","unstructured":"Murakami S, Ono A, Kawasaki A, Takenaga T, Ito T. Taurine attenuates the development of hepatic steatosis through the inhibition of oxidative stress in a model of nonalcoholic fatty liver disease in vivo and in vitro. Amino Acids. 2018;509:1279\u201388.","journal-title":"Amino Acids."},{"key":"9809_CR39","volume-title":"Toxicity testing in the 21st century: a vision and a strategy","author":"National Research Council","year":"2007","unstructured":"National Research Council. Toxicity testing in the 21st century: a vision and a strategy. National Academies Press; 2007."},{"key":"9809_CR40","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1039\/D0AN02212H","volume":"1466","author":"E Olesti","year":"2021","unstructured":"Olesti E, Gonzalez-Ruiz V, Wilks MF, Boccard J, Rudaz S. Approaches in metabolomics for regulatory toxicology applications. Analyst. 2021;1466:1820\u201334.","journal-title":"Analyst."},{"key":"9809_CR41","first-page":"1","volume":"141","author":"IJ Onakpoya","year":"2016","unstructured":"Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Med. 2016;141:1\u201311.","journal-title":"BMC Med."},{"key":"9809_CR42","first-page":"1","volume":"91","author":"S Plummer","year":"2019","unstructured":"Plummer S, Wallace S, Ball G, Lloyd R, Schiapparelli P, Qui\u00f1ones-Hinojosa A, Hartung T, Pamies D. A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine. Sci Rep. 2019;91:1\u201311.","journal-title":"Sci Rep."},{"key":"9809_CR43","first-page":"1","volume":"61","author":"A Prokesch","year":"2016","unstructured":"Prokesch A, Pelzmann HJ, Pessentheiner A, Huber K, Madreiter-Sokolowski C, Drougard A, Schittmayer M, Kolb D, Magnes C, Trausinger G. N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes. Sci Rep. 2016;61:1\u201312.","journal-title":"Sci Rep."},{"key":"9809_CR44","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1007\/s00204-017-2079-6","volume":"922","author":"T Ramirez","year":"2018","unstructured":"Ramirez T, Strigun A, Verlohner A, Huener HA, Peter E, Herold M, Bordag N, Mellert W, Walk T, Spitzer M, Jiang X, Sperber S, Hofmann T, Hartung T, Kamp H, van Ravenzwaay B. Prediction of liver toxicity and mode of action using metabolomics in vitro in HepG2 cells. Arch Toxicol. 2018;922:893\u2013906.","journal-title":"Arch Toxicol."},{"key":"9809_CR45","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/s41551-020-0539-4","volume":"44","author":"DJ Richards","year":"2020","unstructured":"Richards DJ, Li Y, Kerr CM, Yao J, Beeson GC, Coyle RC, Chen X, Jia J, Damon B, Wilson R. Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nat Biomed Eng. 2020;44:446\u201362.","journal-title":"Nat Biomed Eng."},{"key":"9809_CR46","first-page":"1","volume":"121","author":"A Ruiz-Aracama","year":"2011","unstructured":"Ruiz-Aracama A, Peijnenburg A, Kleinjans J, Jennen D, van Delft J, Hellfrisch C, Lommen A. An untargeted multi-technique metabolomics approach to studying intracellular metabolites of HepG2 cells exposed to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. BMC Genom. 2011;121:1\u201319.","journal-title":"BMC Genom."},{"issue":"831-846","key":"9809_CR47","first-page":"e810","volume":"1603","author":"T Shinozawa","year":"2021","unstructured":"Shinozawa T, Kimura M, Cai Y, Saiki N, Yoneyama Y, Ouchi R, Koike H, Maezawa M, Zhang R-R, Dunn A. High-fidelity drug-induced liver injury screen using human pluripotent stem cell\u2013derived organoids. Gastroenterology. 2021;1603(831-846):e810.","journal-title":"Gastroenterology."},{"key":"9809_CR48","first-page":"2","volume":"2","author":"R Suzuki","year":"2019","unstructured":"Suzuki R, Terada Y, Shimodaira H. Pvclust: hierarchical clustering with P-values via multiscale bootstrap resampling, [code]. R Package Ver. 2019;2:2.","journal-title":"R Package Ver."},{"key":"9809_CR49","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1093\/toxsci\/kfi090","volume":"842","author":"D Staskal","year":"2005","unstructured":"Staskal D, Diliberto J, Devito M, Birnbaum L. Inhibition of human and rat CYP1A2 by TCDD and dioxin-like chemicals. Toxicol Sci. 2005;842:225\u201331.","journal-title":"Toxicol Sci."},{"key":"9809_CR50","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.3390\/diagnostics11112053","volume":"1111","author":"DM Tanase","year":"2021","unstructured":"Tanase DM, Gosav EM, Petrov D, Jucan AE, Lacatusu CM, Floria M, Tarniceriu CC, Costea CF, Ciocoiu M, Rezus C. Involvement of ceramides in non-alcoholic fatty liver disease (Nafld) atherosclerosis (ats) development: Mechanisms and therapeutic targets. Diagnostics. 2021;1111:2053.","journal-title":"Diagnostics."},{"key":"9809_CR51","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1021\/acs.jproteome.5b00354","volume":"148","author":"EA Th\u00e9venot","year":"2015","unstructured":"Th\u00e9venot EA, Roux A, Xu Y, Ezan E, Junot C. Analysis of the human adult urinary metabolome variations with age, body mass index, and gender by implementing a comprehensive workflow for univariate and OPLS statistical analyses. J Proteome Res. 2015;148:3322\u201335.","journal-title":"J Proteome Res."},{"key":"9809_CR52","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1093\/toxsci\/kfm092","volume":"981","author":"RS Thomas","year":"2007","unstructured":"Thomas RS, Allen BC, Nong A, Yang L, Bermudez E, Clewell HJ III, Andersen ME. A method to integrate benchmark dose estimates with genomic data to assess the functional effects of chemical exposure. Toxicol Sci. 2007;981:240\u20138.","journal-title":"Toxicol Sci."},{"key":"9809_CR53","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/ieam.4429","volume":"176","author":"J van Dijk","year":"2021","unstructured":"van Dijk J, Leopold A, Flerlage H, van Wezel A, Seiler TB, Enrici MH, Bloor MC. The EU Green Deal's ambition for a toxic-free environment: Filling the gap for science-based policymaking. Integr Environ Assess Manag. 2021;176:1105\u201313.","journal-title":"Integr Environ Assess Manag."},{"key":"9809_CR54","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.toxlet.2014.03.004","volume":"2271","author":"B Van Ravenzwaay","year":"2014","unstructured":"Van Ravenzwaay B, Montoya G, Fabian E, Herold M, Krennrich G, Looser R, Mellert W, Peter E, Strauss V, Walk T. The sensitivity of metabolomics versus classical regulatory toxicology from a NOAEL perspective. Toxicol Lett. 2014;2271:20\u20138.","journal-title":"Toxicol Lett."},{"key":"9809_CR55","doi-asserted-by":"crossref","unstructured":"Van Ravenzwaay B, Kamp H, Montoya-Parra GA, Strauss V, Fabian E, Mellert W, Krennrich G, Walk T, Peter E, Looser R. The development of a database for metabolomics-looking back on ten years of experience. Int J Biotechnol. 2015;141:47\u201368.","DOI":"10.1504\/IJBT.2015.074801"},{"key":"9809_CR56","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.tox.2013.08.011","volume":"312","author":"M Vinken","year":"2013","unstructured":"Vinken M. The adverse outcome pathway concept: a pragmatic tool in toxicology. Toxicology. 2013;312:158\u201365.","journal-title":"Toxicology."},{"key":"9809_CR57","doi-asserted-by":"publisher","first-page":"122","DOI":"10.12688\/wellcomeopenres.14832.1","volume":"3","author":"A Walvekar","year":"2018","unstructured":"Walvekar A, Rashida Z, Maddali H, Laxman S. A versatile LC-MS\/MS approach for comprehensive, quantitative analysis of central metabolic pathways. Wellcome Open Res. 2018;3:122.","journal-title":"Wellcome Open Res."},{"key":"9809_CR58","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1021\/acs.est.9b06379","volume":"545","author":"Z Wang","year":"2020","unstructured":"Wang Z, Walker GW, Muir DC, Nagatani-Yoshida K. Toward a global understanding of chemical pollution: a first comprehensive analysis of national and regional chemical inventories. Environ Sci Technol. 2020;545:2575\u201384.","journal-title":"Environ Sci Technol."},{"key":"9809_CR59","first-page":"1","volume":"71","author":"T Yanagita","year":"2008","unstructured":"Yanagita T, Han S-Y, Hu Y, Nagao K, Kitajima H, Murakami S. Taurine reduces the secretion of apolipoprotein B100 and lipids in HepG2 cells. Lipids Health Dis. 2008;71:1\u20136.","journal-title":"Lipids Health Dis."},{"key":"9809_CR60","doi-asserted-by":"publisher","first-page":"eaal3973","DOI":"10.1126\/scitranslmed.aal3973","volume":"10429","author":"M Zampieri","year":"2018","unstructured":"Zampieri M, Szappanos B, Buchieri MV, Trauner A, Piazza I, Picotti P, Gagneux S, Borrell S, Gicquel B, Lelievre J. High-throughput metabolomic analysis predicts mode of action of uncharacterized antimicrobial compounds. Sci Transl Med. 2018;10429:eaal3973.","journal-title":"Sci Transl Med."},{"key":"9809_CR61","doi-asserted-by":"publisher","first-page":"6856","DOI":"10.1093\/jxb\/erab361","volume":"7220","author":"Y Zheng","year":"2021","unstructured":"Zheng Y, Cabassa-Hourton C, Planchais S, Lebreton S, Savour\u00e9 A. The proline cycle as an eukaryotic redox valve. J Exp Bot. 2021;7220:6856\u201366.","journal-title":"J Exp Bot."}],"container-title":["Cell Biology and Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10565-023-09809-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10565-023-09809-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10565-023-09809-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T03:05:55Z","timestamp":1701486355000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10565-023-09809-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,4]]},"references-count":61,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["9809"],"URL":"https:\/\/doi.org\/10.1007\/s10565-023-09809-6","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2377388\/v1","asserted-by":"object"}]},"ISSN":["0742-2091","1573-6822"],"issn-type":[{"value":"0742-2091","type":"print"},{"value":"1573-6822","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,4]]},"assertion":[{"value":"14 December 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors have no conflicts of interest to declare. BASF may use some of the presented technologies for product development in the future.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}