title: Aminotriazole alleviates acetaminophen poisoning via downregulating P450 2E1 and suppressing inflammation.
abstract: Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Jiashuo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology, Chongqing Medical University, Chongqing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ai
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Ge
authors.affiliation: Hospital of Chongqing University of Arts and Sciences, Chongqing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dai
authors.affiliation: Laboratory of Stem cell and Tissue Engineering, Chongqing Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Che
authors.affiliation: Department of Pharmacology, Chongqing Medical University, Chongqing, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000640:Amitrole / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D006861:Hydrogen Peroxide; D007249:Inflammation / Q000517:prevention & control*; D007928:Lethal Dose 50; D008099:Liver / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D002374:Catalase; D009195:Peroxidase; D019392:Cytochrome P-450 CYP2E1; D000637:Transaminases; D000640:Amitrole