Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity

摘要: Morphological changes in mitochondria are observed early the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been both vivo vitro following exposure to AA. This study examined effects AA on respiration evaluated effectiveness ofN-acetyl-L-cysteine (NAC) protecting against respiratory dysfunction. Mitochondria were isolated from livers fasted, male CD-1 mice 0, 0.5, 1, 1.5 or 2 h after administration a hepatotoxic dose (750 mg/kg). Glutamate- succinate-supported subsequently assessed by polarographic measurement state 3 (ADP-stimulated) 4 (resting) rates oxygen consumption determination corresponding control ratios (RCR: 3/state 4) ADP:O ratios. Hepatotoxicity was histologically measuring plasma alanine aminotransferase (ALT) activity. The earliest sign this significant decrease ratio for oxidation glutamate 1 post-dosing. At post-dosing RCRs glutamate- significantly decreased. All parameters measured decreased, with exception which increased, administration. Thus, inhibition preceded overt hepatic necrosis, indicated an elevation ALT activity, not until In addition, correlated morphological alterations. Inhibition therefore appears be event AA-induced hepatotoxicity. Cotreatment NAC (1200 mg/kg) completely prevented impairment development histopathologic damage. protection afforded these experiments indicates thatN-acetyl-p-benzoquinone imine (NAPQI), reactive metabolite AA, is responsible inhibitory effects, suggests that makes important, if essential, contribution