Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Journal Article · Sat May 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.01.008· OSTI ID:21344945

Gray, Joshua P ^[1]; Joseph, Laurie B; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir ^[2]; Laskin, Jeffrey D ^[3]; Laskin, Debra L ^[2]

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1. Department of Science, United States Coast Guard Academy, New London, CT 06320 (United States)
2. Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)
3. Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States)

Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

• OSTI ID: 21344945
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.01.008; PII: S0041-008X(10)00019-0; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

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60 APPLIED LIFE SCIENCES
AMINOTRANSFERASES
CELL PROLIFERATION
GENES
GENOTYPE
GLUTATHIONE
LIVER
LYMPHOKINES
MESSENGER-RNA
METABOLISM
MONOCYTES
PATHOGENESIS
PROLIFERATION
SUPEROXIDE DISMUTASE
TOXICITY
TRANSGENIC MICE
ANIMALS
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BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
GLANDS
GROWTH FACTORS
LEUKOCYTES
MAMMALS
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MICE
MITOGENS
NITROGEN TRANSFERASES
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXIDOREDUCTASES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RNA
RODENTS
TRANSFERASES
TRANSGENIC ANIMALS
VERTEBRATES