化学物質誘発肝障害モデルに対するミトコンドリア標的型抗酸化剤Mito-TEMPOの肝保護効果

抄録

N-acetyl-p-aminophenol (APAP), Concanavalin A (ConA) and Carbon tetrachloride (CCl₄) exposure generated drug induced liver injury models. Overdose of APAP is the most common cause of acute liver failure, as it induced mitochondrial oxidative stress and hepatic necroptosis. Also, ConA and CCl₄ are causing immune-mediated liver injury and centrilobular necrosis, respectively. We conducted this study to evaluate the effects of Mito-TEMPO (Mito-T) on acute liver injury models in mice. An injection of Mito-T (20 mg/kg) after 1h of APAP (400 mg/kg) administration markedly inhibited the elevation of serum transaminase activity but was not able to attenuate the ConA (12.5 mg/kg) and CCl₄ (0.025 mL/kg) hepatotoxicity in C57BL/6J mice. Mito-T significantly reduced the parameters of APAP derived oxidative stress, such as mitochondrial radical production and nitrotyrosine formation in mouse liver; though the decreased glutathione (GSH) level and c-Jun N-terminal Kinases (JNK) activation were not suppressed in liver. In addition, Mito-T was hepatoprotective after 4 hours of APAP ingestion, whereas, N-acetyl-L-cysteine, the only recognized therapeutic agent against APAP hepatotoxicity, became less effective with the time lapse.

We demonstrated that Mito-T alleviates mitochondrial oxidative stress and suppresses the APAP-induced liver injury in mice. The results suggest that Mito-T could be a promising novel therapeutic agent for APAP overdosed liver injury.