Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands

Xenobiotics induce the transcription of cytochromes P450 (CYPs) 2B and 3A t hrough the constitutive androstane receptor (CAR; NR1I3) and pregnane X rec eptor (PXR; NR1I2), respectively, In this report, we have systematically co mpared a series of xenobiotics and natural steroids for their effects on mo use and human CAR and PXR, Our results demonstrate dual regulation of PXR a nd CAR by a subset of compounds that affect CYP expression, Moreover, there are marked pharmacological differences between the mouse (m) and human (h) orthologs of both CAR and PXR, For example, the planar hydrocarbon 1,4-bis [2-(3,5-dichloropyridyl-oxy)]benzene activates mCAR and hPXR but has little or no activity on hCAR and mPXR, In contrast, the CAR deactivator androsta nol activates both mouse and human PXR, Similarly, the PXR activator clotri mazole is a potent deactivator of hCAR, Using radioligand binding and fluor escence resonance energy transfer assays, we demonstrate that several of th e compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors, Our results suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse comp ounds, Moreover, our findings underscore the complexity in the physiologic response to xenobiotics.