Acetaminophen-induced hepatic injury in mice: the role of lipid peroxidation and effects of pretreatment with coenzyme Q10 and alpha-tocopherol.
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.
Amimoto
T
T
Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
Matsura
T
T
Koyama
S Y
SY
Nakanishi
T
T
Yamada
K
K
Kajiyama
G
G
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003067:Coenzymes; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010084:Oxidation-Reduction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology*
D003067:Coenzymes; D017392:Thiobarbituric Acid Reactive Substances; D014451:Ubiquinone; D014810:Vitamin E; D000082:Acetaminophen; D000410:Alanine Transaminase; C024989:coenzyme Q10; D005978:Glutathione