The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models

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.

Hepatoprotective Effect of Mitochondria-Targeted Antioxidant Mito-TEMPO against Lipopolysaccharide-Induced Liver Injury in Mouse

“…Mito-TEMPO (Sigma, USA) was intraperitoneally injected at a dose of 20 mg/kg body weight 1 h prior to LPS injection. The dosage of Mito-TEMPO is comparable with previous studies [ 28 , 29 ]. Animals were euthanized 24 h after LPS administration, and whole blood and liver samples were harvested for analysis.…”

mito-TEMPO Attenuates Oxidative Stress and Mitochondrial Dysfunction in Noise-Induced Hearing Loss via Maintaining TFAM-mtDNA Interaction and Mitochondrial Biogenesis

“…A previous study demonstrated that mito-TEMPO (MT) can ameliorate renal fibrosis by reducing oxidative stress, mitochondrial dysfunction, and inflammation (Liu et al, 2018 ). In addition, recent studies have shown that MT has a protective effect against acetaminophen-induced hepatotoxicity with a wider therapeutic time window than N-acetyl-L-cysteine (NAC; Du et al, 2017 ; Abdullah-Al-Shoeb et al, 2020 ). Systemic administration of MT was able to alleviate ischemic brain damage in rats (Li et al, 2018 ).…”

Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation

“…All mice were sacrificed 24 h after APAP treatment, after which their blood and liver tissues were isolated for further analysis. The dosages of kahweol and APAP were determined based on previous studies [8,12]. All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Daegu Catholic University Medical Center (approval number: DCIAFCR-200507-05-Y, approval date: 7 May 2020).…”