{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:41:23Z","timestamp":1791013283169,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T00:00:00Z","timestamp":1687132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Winthrop P. Rockefeller Cancer Institute","award":["R01 GM140365"],"award-info":[{"award-number":["R01 GM140365"]}]},{"name":"Winthrop P. Rockefeller Cancer Institute","award":["P20 GM10095"],"award-info":[{"award-number":["P20 GM10095"]}]},{"name":"Winthrop P. Rockefeller Cancer Institute","award":["T32 GM106999"],"award-info":[{"award-number":["T32 GM106999"]}]},{"name":"AASLD Foundation","award":["R01 GM140365"],"award-info":[{"award-number":["R01 GM140365"]}]},{"name":"AASLD Foundation","award":["P20 GM10095"],"award-info":[{"award-number":["P20 GM10095"]}]},{"name":"AASLD Foundation","award":["T32 GM106999"],"award-info":[{"award-number":["T32 GM106999"]}]},{"name":"National Institutes of Health","award":["R01 GM140365"],"award-info":[{"award-number":["R01 GM140365"]}]},{"name":"National Institutes of Health","award":["P20 GM10095"],"award-info":[{"award-number":["P20 GM10095"]}]},{"name":"National Institutes of Health","award":["T32 GM106999"],"award-info":[{"award-number":["T32 GM106999"]}]},{"name":"Tobacco Settlement Proceeds Act of 2000","award":["R01 GM140365"],"award-info":[{"award-number":["R01 GM140365"]}]},{"name":"Tobacco Settlement Proceeds Act of 2000","award":["P20 GM10095"],"award-info":[{"award-number":["P20 GM10095"]}]},{"name":"Tobacco Settlement Proceeds Act of 2000","award":["T32 GM106999"],"award-info":[{"award-number":["T32 GM106999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Livers"],"abstract":"<jats:p>Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model.<\/jats:p>","DOI":"10.3390\/livers3020022","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T03:02:13Z","timestamp":1687230133000},"page":"310-321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Role of Cytochrome P450 3A4-Mediated Metabolism in Sorafenib and Lapatinib Hepatotoxicity"],"prefix":"10.3390","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0401-0463","authenticated-orcid":false,"given":"Mitchell R.","family":"McGill","sequence":"first","affiliation":[{"name":"Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Pharmacology & Toxicology and Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihong","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-3878","authenticated-orcid":false,"given":"Francesca V.","family":"LoBianco","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3594-6835","authenticated-orcid":false,"given":"Mary A.","family":"Schleiff","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8574-4102","authenticated-orcid":false,"given":"Nukhet","family":"Aykin-Burns","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-8187","authenticated-orcid":false,"given":"Grover P.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.drudis.2015.07.008","article-title":"Small-Molecule Kinase Inhibitors: An Analysis of FDA-Approved Drugs","volume":"21","author":"Wu","year":"2016","journal-title":"Drug Discov. 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