ACETAMINOPHEN-INDUCED HEPATIC-INJURY IN MICE - THE ROLE OF LIPID-PEROXIDATION AND EFFECTS OF PRETREATMENT WITH COENZYME Q(10) AND ALPHA-TOCOPHEROL

This study was performed to determine whether oxidative stress contrib uted to the initiation or progression of hepatic injury produced by ac etaminophen (APAP). Treatment of fasted mice with APAP (400 mg/kg, IP) led to hepatic injury as indicated by a marked elevation of plasma al anine aminotransferase (ALT). APAP caused an increased amount of thiob arbituric acid-reactive substance (TBARS), which was accompanied by a loss of reduced forms of coenzyme Q(9) (CoQ(9)H(2)) and coenzyme Q(10) (CoQ(10)H(2)) functioning as antioxidants. APAP also markedly decreas ed hepatic reduced glutathione (GSH) levels. Pretreatment with CoQ(10) (5 mg/kg, IV) reduced hepatic TBARS levels to 30% and plasma ALT leve ls to 26% of placebo pretreatment levels without affecting hepatic GSH levels at 3 h of APAP treatment. alpha-Tocopherol (alpha-Toc) (20 mg/ kg, IV) pretreatment also reduced hepatic TBARS levels to 13% and plas ma ALT levels to 27% of placebo pretreatment levels without affecting hepatic GSH levels. These results suggest that oxidative stress follow ed by lipid peroxidation might play a role in the pathogenesis of APAP -induced hepatic injury, and pretreatment with lipid-soluble antioxida nts such as CoQ(10) and alpha-Toc can limit hepatic injury produced by APAP.