Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.
Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.
Research Institute for Biomedical Sciences, Tokyo University of Science.
Tomoya
T
Arai
Ryo
R
Koyama
Makoto
M
Yuasa
Daisuke
D
Kitamura
Ryushin
R
Mizuta
D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000171:Acrolein / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D062787:Drug Overdose; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D015080:Mesna / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017382:Reactive Oxygen Species; D000082:Acetaminophen; D000171:Acrolein; D015080:Mesna; D000111:Acetylcysteine