| Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity. | |
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MedLine Citation:
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PMID: 20100502 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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(-/-)) 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(-/-) 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(-/-) 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(-/-) mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1(-/-) 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. |
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Authors:
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Carol R Gardner; Joshua P Gray; Laurie B Joseph; Jessica Cervelli; Nicole Bremer; Yunjung Kim; Vladimir Mishin; Jeffrey D Laskin; Debra L Laskin |
Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2010-01-25 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 245 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-03 Completed Date: 2010-06-03 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 36-46 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA. cgardner@eohsi.rutgers.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetaminophen
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toxicity* Animals Antioxidants / metabolism Caveolin 1 / genetics, physiology* Cell Proliferation / drug effects Chemokine CCL2 / metabolism Inflammation / metabolism Inflammation Mediators / metabolism Interleukin-1 / metabolism Interleukin-10 / metabolism Liver / drug effects*, metabolism Male Mice Mice, Knockout |
| Grant Support | |
ID/Acronym/Agency:
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AR055073/AR/NIAMS NIH HHS; CA132634/CA/NCI NIH HHS; ES004738/ES/NIEHS NIH HHS; ES005022/ES/NIEHS NIH HHS; GM034310/GM/NIGMS NIH HHS; P30 ES005022-199008/ES/NIEHS NIH HHS; P30 ES005022-209008/ES/NIEHS NIH HHS; R01 CA132624-01/CA/NCI NIH HHS; R01 CA132624-02/CA/NCI NIH HHS; R01 ES004738-15/ES/NIEHS NIH HHS; R01 ES004738-16A2/ES/NIEHS NIH HHS; R01 ES004738-17/ES/NIEHS NIH HHS; R01 GM034310-20/GM/NIGMS NIH HHS; R01 GM034310-21A1/GM/NIGMS NIH HHS; R01 GM034310-22/GM/NIGMS NIH HHS; R01 GM034310-23/GM/NIGMS NIH HHS; R01 GM034310-24/GM/NIGMS NIH HHS; U54 AR055073-03/AR/NIAMS NIH HHS; U54 AR055073-04/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Caveolin 1; 0/Chemokine CCL2; 0/Inflammation Mediators; 0/Interleukin-1; 103-90-2/Acetaminophen; 130068-27-8/Interleukin-10 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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