title: Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway.
abstract: Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis--were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen-induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology.
authors.affiliation: Department of Natural Sciences, Western University "Vasile Goldis" of Arad, Romania; Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania.
authors.forename: Maria
authors.initials: M
authors.lastname: Suciu
authors.affiliation: Regional Center for Transplant & Immunology, County Clinical Emergency Hospital Timisoara, 10 Iosif Bulbuca Blvd., 300736 Timisoara, Romania.
authors.forename: Alexandra T
authors.initials: AT
authors.lastname: Gruia
authors.affiliation: Regional Center for Transplant & Immunology, County Clinical Emergency Hospital Timisoara, 10 Iosif Bulbuca Blvd., 300736 Timisoara, Romania; Faculty of Animal Sciences and Biotechnologies, Banat's University of Agricultural Sciences and Veterinary Medicine "King Michael I of Romania" from Timisoara, Timis, Romania. Electronic address: nicadragos@gmail.com.
authors.forename: Dragos V
authors.initials: DV
authors.lastname: Nica
authors.affiliation: Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania.
authors.forename: Seyed M R
authors.initials: SM
authors.lastname: Azghadi
authors.affiliation: Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania; INCD "Victor Babes" Bucuresti, Romania.
authors.forename: Ani A
authors.initials: AA
authors.lastname: Mic
authors.affiliation: Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Mic
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology*; D015777:Eicosanoids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015777:Eicosanoids; D005230:Fatty Acids, Nonesterified; D000082:Acetaminophen
keywords: Acetaminophen; Cyclooxygenase; Eicosanoids; Free fatty acids; Liver