title: Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.
abstract: Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Abdulrazaq
authors.initials: A
authors.lastname: Alanazi
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Saleh G
authors.initials: SG
authors.lastname: Algfeley
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Al-Hosaini
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Faisal
authors.initials: F
authors.lastname: Imam
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Nagi
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000633:toxicity*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D005978:Glutathione; D007249:Inflammation / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D000082:Acetaminophen; C524865:carfilzomib; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D005978:Glutathione
keywords: COX-II and iNOS
  ; TNF-α; acetaminophen; carfilzomib; hepatotoxicity; oxidative and nitrosative stress