title: Hepatic Overexpression of Annexin A1 and A2 in Thioacetamide-Primed Mice Protects Them Against Acetaminophen-Induced Liver Failure and Death.
abstract: Compensatory tissue repair (CTR) in thioacetamide (TA)-primed rats protects them against acetaminophen (APAP)-induced lethality. This study was aimed at investigating the mechanisms of CTR-mediated heteroprotection in mice. Male Swiss Webster mice received a priming dose of TA (40 mg/kg body weight [BW] in 10 mL distilled water [DW]/kg BW, intraperitoneally [IP]). Thioacetamide-induced liver injury, CTR, and expression of annexin A1 and A2 (ANX1 and ANX2), the endogenous inhibitors of the death protein secretory phospholipase A2 (sPLA2), were measured over a time course of 84 hours after TA priming. Both centrilobular necrosis and CTR peaked at 36 hours after TA priming as indicated by significantly increased plasma alanine transaminase (ALT) and aspartate transaminase (AST) activities, liver histology, and proliferating cell nuclear antigen immunostaining. Thioacetamide priming resulted in the overexpression of ANX1 and ANX2 at 36 to 84 hours and 12 to 60 hours, respectively. A lethal dose of APAP (600 mg/kg BW in 10 mL 0.45% NaCl/kg BW, IP) was given at 12, 24, or 36 hours after TA-priming. Thioacetamide priming did not affect the rise in plasma ALT, AST, sPLA2, and arachidonic acid levels seen at 2 hours after the APAP overdose. Neither these biochemical parameters nor histology suggested any escalation of hepatic injury at later time points (12 and 24 hours after APAP overdose), consistent with 100% survival of the TA + APAP-treated mice compared to DW + APAP-treated mice, which had 100% mortality. Inhibition of ANX1 and ANX2 biosynthesis using cycloheximide (40 mg/kg BW in 5 mL DW/kg BW, IP) abolished this heteroprotection. Our data indicate that hepatic overexpression of ANX1 and ANX2 inhibits APAP-induced expansion of liver injury.
authors.affiliation: Department of Toxicology, College of Health and Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USA.
authors.forename: Vivekkumar P
authors.initials: VP
authors.lastname: Dadhania
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research (NCTR), Jefferson, AR, USA.
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research (NCTR), Jefferson, AR, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.affiliation: Department of Toxicology, College of Health and Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USA mehendale@ulm.edu.
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000082:Acetaminophen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D017306:Annexin A2 / Q000378:metabolism*; D001219:Aspartate Aminotransferases / Q000097:blood; D002462:Cell Membrane / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D013853:Thioacetamide
chemical_list: D017305:Annexin A1; D017306:Annexin A2; C573274:annexin A1, mouse; D013853:Thioacetamide; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione
keywords: Annexin A1; Annexin A2; Heteroprotection; Liver failure; Secretory phospholipase A2; Tissue repair