Conclusion: This is the first study to illustrate that CP-690550 solubility dmso 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;) Altered states of drug metabolism were first noticed by physicians over 30 years ago when virally infected patients would exhibit new or pronounced adverse reactions to pharmacologic agents.1 Such perturbations in drug metabolism have been linked to the effects of infections or inflammatory stimuli on altering the activities and expression of various hepatic cytochrome P450 (CYP) enzymes.2, 3 CYPs are responsible for pharmacological activation or inactivation of many drugs as well as their clearance from

the circulation.4 In light of the considerable progress in our understanding of host antiviral innate immune responses and pathways during the last decade, it is surprising that little recent research has been conducted on the mechanisms by which CYP enzymes are modulated during viral infections. Hepatic CYPs have been shown to be affected differently in response to various inflammatory stimuli.4 This selectivity is important clinically and implies the existence INCB024360 mw of multiple mechanisms for CYP regulation. We previously demonstrated a novel mechanism by which viral infection leads to transcriptional down-regulation of nuclear hormone receptor retinoid X receptor α (RXRα) and its downstream CYP enzymes required for aspirin (ASA) metabolism.5 Our results provided an explanation for how ASA consumption can cause Reye’s syndrome, a condition where children with viral infections develop hepatotoxicity and neurological side effects.6 Given these adverse effects of ASA in patients with viral infections, acetaminophen (APAP) is often the first line of therapy to manage pain in children.7 In this study we evaluate the effects of crosstalk between nuclear hormone receptors and antiviral

pathways on metabolism and toxicity of APAP. APAP-induced toxicity is the leading cause of acute hepatic failure in the United States and many other Myosin developed countries worldwide.8 APAP is metabolized by CYP family members CYP1A2, CYP2E1, and CYP3A11 (murine homolog of human CYP3A4) into N-acetyl-p-benzoquinone-imine (NAPQI) in mice.9, 10 NAPQI is a highly reactive intermediate that is normally conjugated to glutathione by glutathione S-transferase enzymes in order to become more excretable.11 Accumulation of NAPQI causes cell death and toxicity through covalent binding to cysteine groups on proteins and formation of APAP-protein adducts. The generation of these APAP-protein adducts has been correlated with hepatotoxicity through oxidation of NAPQI-conjugated proteins.12 Among the CYP enzymes involved in NAPQI generation, CYP3A isoforms and CYP1A2 are subject to regulation by nuclear hormone receptors.