title: Effect of alcohol on diethylnitrosamine-induced hepatic toxicity: Critical role of ROS, lipid accumulation, and mitochondrial dysfunction.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women worldwide. Chronic heavy alcohol consumption is a major risk factor for the development of HCC. However, the mechanism underlying the direct association between alcohol consumption and HCC is far from completely understood. In the present study, we investigated the effect of chronic consumption of alcohol on diethylnitrosamine (DEN)-induced cytotoxicity, which was essential for the malignant transformation. We showed that alcohol deceased survival of mice treated by DEN and promoted DEN-induced toxicity and hepatic injury. In addition, alcohol promoted DEN-induced increase of proinflammatory factors, collagen content and fibrosis-related genes, including collagen1, 3 and 4, TMIP1, TIMP2 and TGFβ1, and compensatory proliferation. Alcohol may increase alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1) expression, enhanced reactive oxygen species (ROS) generation, and resulted in a vicious circle between ROS generation, lipid accumulation, and mitochondrial dysfunction, aggravating liver injury and toxicity in DEN-treated mice. These results demonstrated that the combination of alcohol and carcinogens could aggravate carcinogen-induced cytotoxicity in the early phase of rumourigenesis through ADH and CYP2E1-generated ROS and the resultant cytotoxic process. The present study provided direct experimental evidence for alcohol-promoted toxicity and hepatic injury in carcinogen (DEN)-treated mice.
authors.affiliation: The First Student Brigade, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Quangui
authors.initials: Q
authors.lastname: Sun
authors.affiliation: The First Student Brigade, Forth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Long
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xinwang@fmmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China. Electronic address: cx-hai@fmmu.edu.cn.
authors.forename: Chunxu
authors.initials: C
authors.lastname: Hai
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004052:Diethylnitrosamine / Q000633:toxicity*; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002273:Carcinogens; D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine
keywords: Alcohol; Diethylnitrosamine; Hepatic injury; Mitochondrial dysfunction; ROS