{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:23:00Z","timestamp":1788492180838,"version":"build-2803163510"},"reference-count":125,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, Center for Biochemical Research Excellence","award":["PR20RR017695"],"award-info":[{"award-number":["PR20RR017695"]}]},{"name":"The Program of the European Union FP7 HTP-GlycoMet","award":["PR20RR017695"],"award-info":[{"award-number":["PR20RR017695"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We examined proteomic profiles of rat liver extracellular vesicles (EVs) shed following treatment with a sub-toxic dose (500 mg\/kg) of the pain reliever drug, acetaminophen (APAP). EVs representing the entire complement of hepatic cells were isolated after perfusion of the intact liver and analyzed with LC-MS\/MS. The investigation was focused on revealing the function and cellular origin of identified EVs proteins shed by different parenchymal and non-parenchymal liver cells and their possible role in an early response of this organ to a toxic environment. Comparison of EV proteomic profiles from control and APAP-treated animals revealed significant differences. Alpha-1-macroglobulin and members of the cytochrome P450 superfamily were highly abundant proteins in EVs shed by the normal liver. In contrast, proteins like aminopeptidase N, metalloreductase STEAP4, different surface antigens like CD14 and CD45, and most members of the annexin family were detected only in EVs that were shed by livers of APAP-treated animals. In EVs from treated livers, there was almost a complete disappearance of members of the cytochrome P450 superfamily and a major decrease in other enzymes involved in the detoxification of xenobiotics. Additionally, there were proteins that predominated in non-parenchymal liver cells and in the extracellular matrix, like fibronectin, receptor-type tyrosine-protein phosphatase C, and endothelial type gp91. These differences indicate that even treatment with a sub-toxic concentration of APAP initiates dramatic perturbation in the function of this vital organ.<\/jats:p>","DOI":"10.3390\/ijms23168870","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T02:42:53Z","timestamp":1660099373000},"page":"8870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Possible Role of Extracellular Vesicles in Hepatotoxicity of Acetaminophen"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8790-9465","authenticated-orcid":false,"given":"Martina","family":"\u0160rajer Gajdo\u0161ik","sequence":"first","affiliation":[{"name":"Department of Chemistry, Josip Juraj Strossmayer University, 31000 Osijek, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anamarija","family":"Kova\u010d Pei\u0107","sequence":"additional","affiliation":[{"name":"General Hospital Josip Ben\u010devi\u0107, 35000 Slavonski Brod, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Begi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Grb\u010di\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Brilliant","sequence":"additional","affiliation":[{"name":"Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI 02903, USA"},{"name":"Warren Alpert Medical School, Brown University, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas C.","family":"Hixson","sequence":"additional","affiliation":[{"name":"Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI 02903, USA"},{"name":"Warren Alpert Medical School, Brown University, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djuro","family":"Josi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University Juraj Dobrila of Pula, 52100 Pula, Croatia"},{"name":"Warren Alpert Medical School, Brown University, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1055\/s-2007-1007247","article-title":"Classification, Etiology, and Considerations of Outcome in Acute Liver Failure","volume":"16","author":"Williams","year":"1996","journal-title":"Semin. 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