title: Quinocetone-induced Nrf2/HO-1 pathway suppression aggravates hepatocyte damage of Sprague-Dawley rats.
abstract: Quinocetone (3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide, QCT) is a widely used veterinary drug in PR China that promotes feed efficiency and growth of various animals. However, its potential toxicity has been concerned recently. In the present study, we investigated QCT-induced hepatocyte changes and its related mechanism, especially the expression of Nrf2/HO-1 pathway. Oxidative stress induced by QCT in hepatocyte led to DNA damage, inflammation and apoptosis. Nevertheless, hepatocyte has a self-repair system to protect itself from oxidative stress. In the 50 mg/kg/day QCT group, the morphology and function of liver were approximately maintained on normal level, which indicated that the damaged cell might have a self-repair mechanism. Notably, nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway plays a critical role in protecting cells against reactive oxygen species (ROS) generation. However, higher doses of QCT (800 mg/kg/day and 2400 mg/kg/day) inhibited the expression of Nrf2/HO-1 pathway, which resulted in excessive ROS generation and irreversible oxidative DNA damage, inflammation and apoptosis. In conclusion, although QCT-induced oxidative stress activates the expression of Nrf2/HO-1 pathway initially, persistent QCT exposure will inhibit this expression and aggravate hepatocyte damage. Simultaneously, inflammation and apoptosis continues to progress, liver dysfunction and tissue damage will be occurred eventually.
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Mengjing
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
authors.affiliation: Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China. Electronic address: yanhong@mails.tjmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China. Electronic address: lgliu@mails.tjmu.edu.cn.
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011810:Quinoxalines / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011810:Quinoxalines; D017382:Reactive Oxygen Species; C502851:quinocetone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051547:Heme Oxygenase-1; D003849:Deoxyguanosine
keywords: Nrf2/HO-1 pathway; Oxidative stress; Quinocetone