These authors contributed equally to this work.
Article first published online: 25 MAY 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 53, Issue 6, pages 2042–2052, June 2011
How to Cite
Ghaffari, A. A., Chow, E. K., Iyer, S. S., Deng, J. C. and Cheng, G. (2011), Polyinosinic-polycytidylic acid suppresses acetaminophen-induced hepatotoxicity independent of type I interferons and toll-like receptor 3. Hepatology, 53: 2042–2052. doi: 10.1002/hep.24316
A.A. Ghaffari was supported by Microbial Pathogenesis Training Grant T32-AI07323. E.K. Chow was supported by the Ruth L. Kirschstein National Research Award GM07185. Part of this work was also supported by National Institutes of Health research grants R01 AI078389, AI056154, and AI069120.
Potential conflict of interest: Nothing to report.
- Issue published online: 25 MAY 2011
- Article first published online: 25 MAY 2011
- Accepted manuscript online: 23 MAR 2011 09:54AM EST
- Manuscript Accepted: 15 MAR 2011
- Manuscript Received: 16 AUG 2010
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 (polyI:C), leads to decreased acetaminophen (APAP) metabolism and hepatotoxicity. PolyI:C 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 polyI:C on drug metabolism are often attributed to interferon production, we report that polyI:C can decrease APAP metabolism in the absence of the type I interferon receptor. Furthermore, we demonstrate that polyI:C 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 polyI:C affects drug metabolism independent of type I interferon production or in the absence of TLR3 through crosstalk between nuclear receptors and antiviral responses. (HEPATOLOGY 2011;)