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  • Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity.

Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity.

The Journal of pharmacology and experimental therapeutics (2013-06-14)
Lihai Zhang, Terrence Gavin, Brian C Geohagen, Qiang Liu, Katherine J Downey, Richard M LoPachin
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.

MATERIALS
Product Number
Brand
Product Description

Paracetamol, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
2-Acetylcyclopentanone, 98%
Supelco
Acetaminophen solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Acetaminophen, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Acetaminophen, analytical standard
Sigma-Aldrich
Acetaminophen, meets USP testing specifications, 98.0-102.0%, powder
Sigma-Aldrich
Acetaminophen, BioXtra, ≥99.0%