title: Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity.
abstract: Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80-2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40-7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80-2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-p-benzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants.
authors.affiliation: Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: Lihai
authors.initials: L
authors.lastname: Zhang
authors.forename: Terrence
authors.initials: T
authors.lastname: Gavin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Geohagen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Downey
authors.forename: Richard M
authors.initials: RM
authors.lastname: LoPachin
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000506:poisoning*; D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D011789:Quantum Theory
chemical_list: C583588:2-acetylcyclopentanone; D015415:Biomarkers; D007659:Ketones; D000082:Acetaminophen; D000111:Acetylcysteine