Polyinosinic-polycytidylic acid suppresses acetaminophen-induced hepatotoxicity independent of type I interferons and toll-like receptor 3.
Hepatology
; 53(6): 2042-52, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-21433044
ABSTRACT
UNLABELLED Viral infections are often linked to altered drug metabolism in patients; however, the underlying molecular mechanisms remain unclear. Here we describe a mechanism by which activation of antiviral responses by the synthetic double-stranded RNA ligand, polyinosinic-polycytidylic acid (polyIC), leads to decreased acetaminophen (APAP) metabolism and hepatotoxicity. PolyIC administration down-regulates expression of retinoic X receptor-α (RXRα) as well as its heterodimeric partner pregnane X receptor (PXR) in mice. This down-regulation results in suppression of downstream cytochrome P450 enzymes involved in conversion of APAP to its toxic metabolite. Although the effects of polyIC on drug metabolism are often attributed to interferon production, we report that polyIC can decrease APAP metabolism in the absence of the type I interferon receptor. Furthermore, we demonstrate that polyIC can attenuate APAP metabolism through both its membrane-bound receptor, Toll-like receptor 3 (TLR3), as well as cytoplasmic receptors. CONCLUSION:
This is the first study to illustrate that in vivo administration of polyIC affects drug metabolism independent of type I interferon production or in the absence of TLR3 through crosstalk between nuclear receptors and antiviral responses.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
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Interferon Tipo I
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Poli I-C
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Receptor 3 Toll-Like
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Doença Hepática Induzida por Substâncias e Drogas
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Acetaminofen
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article