Acute ethanol pretreatment increases FAS-mediated liver injury in mice: role of oxidative stress and CYP2E1-dependent and -independent pathways.
This study evaluated whether acute ethanol pretreatment potentiates Fas-mediated liver injury and if oxidative stress and CYP2E1 play a role in any enhanced hepatotoxicity. There were 3-fold increases of transaminases and more extensive apoptotic necrosis of hepatocytes and focal hemorrhages of the hepatic lobule in mice treated with Jo2 Fas agonistic antibody plus ethanol compared to saline control or to mice treated with Jo2 or ethanol alone. CYP2E1 catalytic activity and protein were increased 2-fold by the acute ethanol pretreatment. There were 2- and 2.5-fold increases of caspase-8 and caspase-3 activity and 1.6-fold increases of apoptotic-positive cells in the Jo2 plus acute ethanol group compared to the Jo2 alone group. Levels of TNF-alpha, malondialdehyde, 4-hydroxynonenal, protein carbonyl formation, 3-nitrotyrosine protein adducts, and inducible nitric oxide synthase were increased in the Jo2 plus ethanol group. The enhanced hepatotoxicity of Jo2 plus ethanol and the elevated oxidative stress and TNF levels were lower in CYP2E1 knockout mice compared to wild-type mice expressing CYP2E1 but higher than saline controls. Toxicity also declined in mice treated with gadolinium chloride, an inhibitor of the inducible nitric oxide synthase or the antioxidant, N-acetyl-L-cysteine. These data indicate that acute ethanol pretreatment is capable of elevating hepatic apoptosis and liver injury induced by Jo2 Fas agonistic antibody. The enhanced hepatotoxicity involves increased oxidative and nitrosative stress, and appears to be mediated by CYP2E1-dependent and also CYP2E1-independent mechanisms.
Wang
Xiaodong
X
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA. xiaodong.wang@mssm.edu
Cederbaum
Arthur I
AI
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000633:toxicity*
D019014:fas Receptor; D000431:Ethanol; D009195:Peroxidase; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II