title: Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPARalpha with clofibrate.
abstract: The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPARalpha via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. (14)C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAP hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by (3)H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPARalpha was tested. PPARalpha was downregulated in NASH. To investigate whether downregulation of PPARalpha in NASH is the critical mechanism of compromised liver tissue repair, PPARalpha was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPARalpha expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.
authors.affiliation: Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209-0470, USA.
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Donthamsetty
authors.forename: Vishakha S
authors.initials: VS
authors.lastname: Bhave
authors.forename: Mayurranjan S
authors.initials: MS
authors.lastname: Mitra
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000032:analysis; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D019610:Cytoprotection; D004261:DNA Replication; D005234:Fatty Liver / Q000378:metabolism*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D047493:PPAR alpha / Q000096:biosynthesis*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis
chemical_list: D047493:PPAR alpha; D018809:Proliferating Cell Nuclear Antigen; D000082:Acetaminophen; D000255:Adenosine Triphosphate; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase; D002994:Clofibrate