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N-acetyl-L-cysteine (NAC), the only recognized drug against APAP hepatotoxicity, is less effective the later it is administered. This study evaluated the protective effect of mitochondria-specific Mito-TEMPO (Mito-T) on APAP-induced acute liver injury in C57BL\/6J male mice, and a three dimensional (3D)-cell culture model containing the human hepatoblastoma cell line HepG2. The administration of Mito-T (20 mg\/kg, i.p.) 1 h after APAP (400 mg\/kg, i.p.) injection markedly attenuated the APAP-induced elevated serum transaminase activity and hepatic necrosis. However, Mito-T treatment did not affect key factors in the development of APAP liver injury including the activation of c-jun N-terminal kinases (JNK), and expression of the transcription factor C\/EBP homologous protein (CHOP) in the liver. However, Mito-T significantly reduced the APAP-induced increase in the hepatic oxidative stress marker, nitrotyrosine, and DNA fragmentation. Mito-T markedly attenuated cytotoxicity induced by APAP in the HepG2 3D-cell culture model. Moreover, liver regeneration after APAP hepatotoxicity was not affected by Mito-T, demonstrated by no changes in proliferating cell nuclear antigen formation. Therefore, Mito-T was hepatoprotective at the late-stage of APAP overdose in mice.<\/jats:p>","DOI":"10.3390\/antiox9100965","type":"journal-article","created":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T10:19:23Z","timestamp":1602238763000},"page":"965","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9279-1257","authenticated-orcid":false,"given":"Mohammad","family":"Abdullah-Al-Shoeb","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Program for Leading Graduate Schools \u201cHIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program\u201d, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Department of Biochemistry and Molecular Biology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Kikutani","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanami","family":"Namba","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1456-7721","authenticated-orcid":false,"given":"Yuki","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsumi","family":"Irie","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"},{"name":"Program for Leading Graduate Schools \u201cHIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program\u201d, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-4469","authenticated-orcid":false,"given":"Yoichi","family":"Ishitsuka","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2165\/00002018-200528030-00004","article-title":"Tolerability of Paracetamol","volume":"28","author":"Graham","year":"2005","journal-title":"Drug Saf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/pds.1191","article-title":"Estimates of acetaminophen (paracetomal)-associated overdoses in the United States","volume":"15","author":"Nourjah","year":"2006","journal-title":"Pharmacoepidemiol. 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