Secretory phospholipase A{sub 2}-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2

Journal Article · Tue Mar 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.01.013· OSTI ID:21535258

Bhave, Vishakha S; Donthamsetty, Shashikiran ^[1]; Latendresse, John R ^[2]; Cunningham, Michael L ^[3]

---

1. Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA (United States)
2. Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR (United States)
3. NIEHS, Research Triangle Park, NC (United States)

We have previously reported that among the other death proteins, hepatic secretory phospholipase A{sub 2} (sPLA{sub 2}) is a leading mediator of progression of liver injury initiated by CCl{sub 4} in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA{sub 2} released after acetaminophen (APAP) challenge mediates progression of liver injury in wild type (WT) and COX-2 knockout (KO) mice. COX-2 WT and KO mice were administered a normally non lethal dose (400 mg/kg) of acetaminophen. The COX-2 KO mice suffered 60% mortality compared to 100% survival of the WT mice, suggesting higher susceptibility of COX-2 KO mice to sPLA{sub 2}-mediated progression of acetaminophen hepatotoxicity. Liver injury was significantly higher at later time points in the KO mice compared to the WT mice indicating that the abatement of progression of injury requires the presence of COX-2. This difference in hepatotoxicity was not due to increased bioactivation of acetaminophen as indicated by unchanged cyp2E1 protein and covalently bound {sup 14}C-APAP in the livers of KO mice. Hepatic sPLA{sub 2} activity and plasma TNF-{alpha} were significantly higher after APAP administration in the KO mice. This was accompanied by a corresponding fall in hepatic PGE{sub 2} and lower compensatory liver regeneration and repair ({sup 3}H-thymidine incorporation) in the KO mice. These results suggest that hindered compensatory tissue repair and poor resolution of inflammation for want of beneficial prostaglandins render the liver very vulnerable to sPLA{sub 2}-mediated progression of liver injury. These findings are consistent with the destructive role of sPLA{sub 2} in the progression and expansion of tissue injury as a result of continued hydrolytic breakdown of plasma membrane phospholipids of perinecrotic hepatocytes unless mitigated by sufficient co-induction of COX-2.

• OSTI ID: 21535258
• Journal Information: Toxicology and Applied Pharmacology, Vol. 251, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.01.013; PII: S0041-008X(11)00023-8; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
CARBON MONOXIDE
CARBON TETRACHLORIDE
DEATH
HYDROGENASES
INFLAMMATION
LETHAL DOSES
LIVER
LIVER CELLS
MICE
MORTALITY
PHOSPHATES
PROSTAGLANDINS
RATS
REGENERATION
AMINO ACIDS
ANIMAL CELLS
ANIMALS
BODY
CARBON COMPOUNDS
CARBON OXIDES
CARBOXYLIC ACIDS
CHALCOGENIDES
CHLORINATED ALIPHATIC HYDROCARBONS
DIGESTIVE SYSTEM
DOSES
ENZYMES
GLANDS
HALOGENATED ALIPHATIC HYDROCARBONS
MAMMALS
ORGANIC ACIDS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
OXIDES
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PHOSPHORUS COMPOUNDS
PROTEINS
RODENTS
SOMATIC CELLS
SYMPTOMS
VERTEBRATES