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However, hepatic steatosis has never been reported in patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan\u2010induced steatosis might be linked to the high expression of glutathione S\u2010transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan\u2010induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug\u2010induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.<\/jats:p><\/jats:sec>","DOI":"10.1111\/fcp.12951","type":"journal-article","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T10:30:00Z","timestamp":1693823400000},"page":"152-167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug\u2010induced liver injury"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1888-3572","authenticated-orcid":false,"given":"Julien","family":"Allard","sequence":"first","affiliation":[{"name":"Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3282-7435","authenticated-orcid":false,"given":"Simon","family":"Bucher","sequence":"additional","affiliation":[{"name":"Scribe Therapeutics  Alameda California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7417-4690","authenticated-orcid":false,"given":"Pierre\u2010Jean","family":"Ferron","sequence":"additional","affiliation":[{"name":"INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5153-6823","authenticated-orcid":false,"given":"Youenn","family":"Launay","sequence":"additional","affiliation":[{"name":"INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2994-5465","authenticated-orcid":false,"given":"Bernard","family":"Fromenty","sequence":"additional","affiliation":[{"name":"INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2019.1662395"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2017.1360277"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2014.04.005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000028359"},{"issue":"9","key":"e_1_2_9_6_1","first-page":"1015","article-title":"Busulfan conjugation by glutathione S\u2010transferases alpha, mu, and pi","volume":"24","author":"Czerwinski M","year":"1996","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200215666140202214012"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20310"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13185"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics11090440"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250903107764"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0399\u20108320(04)95062\u20102"},{"key":"e_1_2_9_13_1","volume-title":"LiverTox: Clinical and Research Information on Drug\u2010Induced Liver Injury","year":"2012"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.012880"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/6.6.471"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565\u2010020\u201009537\u20101"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24290"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.113860"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2016.04.007"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232137699"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.100.3.965"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/4396403"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20102952(93)90518\u20102"},{"key":"e_1_2_9_24_1","unstructured":"Joss\u00e9R RogueA LambertC.Early target genes of aflatoxin B1 in human hepatic cells. 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