133 Such models bear some limitations because enzymes and transporters may not have similar functions in mouse and human systems and the crosstalk of NRs cannot be sufficiently determined because only one or two genes are humanized.131 PXR and CAR are the most prominent NRs involved in regulation of drug disposition. Other nuclear factors involved in drug metabolism and the defense against oxidative stress are the aryl hydrocarbon receptor (AhR) and nuclear factor-E2-related factor (Nrf2).134 PXR and CAR play important roles in clinically

relevant drug interactions. Prescription drugs activating these NRs can either lead to PF-562271 clinical trial increased clearance and decreased therapeutic efficacy of other drugs or can induce drug bioactivation with formation of reactive intermediate metabolite causing hepatotoxicity.135 Acetaminophen (APAP) hepatotoxicity is a prototypic example for drug interactions due to NR activation. Various inducers of CYP gene expression worsen APAP liver toxicity by increasing phase I oxidation of APAP to the reactive metabolite N-acetyl-p-benzoquinone-imine

(NAPQI).136 Increased APAP toxicity has been reported after administration of the CYP3A inducer dexamethasone and PXR was identified as a further culprit.137 CAR and RXRα also play a role in the pathophysiology of APAP toxicity, because CAR and RXRα knockout mice and mice treated with a CAR antagonist are resistant against APAP toxicity.138,139 In addition, activation of PPARα 3-deazaneplanocin A mw by clofibrate treatment and stimulation of Nrf2 by oleanolic acid has protective properties.140,141 Drugs inhibiting CAR and PXR target gene expression and inducers of RXRα, PPARα, and Nrf2 may represent innovative therapeutic approaches for the treatment of APAP-induced see more liver injury. Taken together, NRs play a key role in drug interactions

and in drug-induced liver injury. Such interactions can cause liver damage even when the drug is not directly hepatotoxic. A variety of transcription factors, including NRs, regulate HBV promoters and enhancers and thereby control HBV pregenomic RNA synthesis and transcription.142 Thus, future antiviral strategies may take advantage of NR effects on viral replication. As summarized in Supporting Table 6, most NRs increase rather than decrease HBV replication. The antiinflammatory effects of NRs should further assist potential direct antiviral effects. FXR, HNF4, and PPARα up-regulate synthesis of pregenomic RNA and viral DNA.143,144 Two FXR response elements in the hepatitis B virus enhancer and core promoter regions have been identified143 and bile acids promote transcription and expression of HBV in hepatic cell lines by way of FXR.145 Thus, bile acids can antagonize the antiviral effects of interferons through promotion of HBV transcription and gene expression.145 In contrast, the PPARγ agonist rosiglitazone has an inhibitory effect on HBV replication in vitro.