title: Polyinosinic-polycytidylic acid suppresses acetaminophen-induced hepatotoxicity independent of type I interferons and toll-like receptor 3.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors: Amir A
authors: AA
authors: Ghaffari
authors: Edward K
authors: EK
authors: Chow
authors: Shankar S
authors: SS
authors: Iyer
authors: Jane C
authors: JC
authors: Deng
authors: Genhong
authors: G
authors: Cheng
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D007370:Interferon Type I / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology / Q000627:therapeutic use*; D000077297:Pregnane X Receptor; D012330:RNA, Double-Stranded / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics; D011987:Receptors, Steroid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015262:Xenobiotics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D000077297:Pregnane X Receptor; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D051196:Toll-Like Receptor 3; D015262:Xenobiotics; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D011070:Poly I-C