Acetaminophen-induced hepatic injury in mice: the role of lipid peroxidation and effects of pretreatment with coenzyme Q10 and alpha-tocopherol.

ABSTRACT

This study was performed to determine whether oxidative stress contributed to the initiation or progression of hepatic injury produced by acetaminophen (APAP). Treatment of fasted mice with APAP (400 mg/kg, I.P.) led to hepatic injury as indicated by a marked elevation of plasma alanine aminotransferase (ALT). APAP caused an increased amount of thiobarbituric acid-reactive substance (TBARS), which was accompanied by a loss of reduced forms of coenzyme Q9 (CoQ9H2) and coenzyme Q10 (CoQ10H2) functioning as antioxidants. APAP also markedly decreased hepatic reduced glutathione (GSH) levels. Pretreatment with CoQ10 (5 mg/kg, I.V.) reduced hepatic TBARS levels to 30% and plasma ALT levels to 26% of placebo pretreatment levels without affecting hepatic GSH levels at 3 h of APAP treatment. alpha-Tocopherol (alpha-Toc) (20 mg/kg, I.V.) pretreatment also reduced hepatic TBARS levels to 13% and plasma ALT levels to 27% of placebo pretreatment levels without affecting hepatic GSH levels. These results suggest that oxidative stress followed by lipid peroxidation might play a role in the pathogenesis of APAP-induced hepatic injury, and pretreatment with lipid-soluble antioxidants such as CoQ10 and alpha-Toc can limit hepatic injury produced by APAP.