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- Title
The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models.
- Authors
Abdullah-Al-Shoeb, Mohammad; Sasaki, Kenta; Kikutani, Saori; Namba, Nanami; Ueno, Keiichi; Kondo, Yuki; Maeda, Hitoshi; Maruyama, Toru; Irie, Tetsumi; Ishitsuka, Yoichi
- Abstract
An overdose of acetaminophen (APAP), the most common cause of acute liver injury, induces oxidative stress that subsequently causes mitochondrial impairment and hepatic necroptosis. 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.
- Subjects
HEPATOTOXICOLOGY; C-Jun N-terminal kinases; PROLIFERATING cell nuclear antigen; CELL culture; LIVER regeneration; TRANSCRIPTION factors
- Publication
Antioxidants, 2020, Vol 9, Issue 10, p965
- ISSN
2076-3921
- Publication type
Article
- DOI
10.3390/antiox9100965