Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor

Cytochromes P450 (P450s) are involved in the oxidative metabolism of a plet hora of structurally unrelated compounds, including therapeutic drugs. Two orphan members of the nuclear receptor superfamily, the pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) have been i mplicated in this phenomenon. In the present study, we examined the transcr iptional regulation of the human CYP2B6 gene. In primary cultures of human hepatocytes, CYP2B6 was highly inducible by a number of compounds known to be human PXR ligands, including rifampicin and hyperforin. PXR was shown to be capable of activating the phenobarbital-responsive enhancer module (PBR EM) region of the CYP2B6 gene, a 51-base-pair enhancer element that mediate s induction of CYP2B6 expression by CAR. The two nuclear receptor-binding m otifs within the PBREM effectively bound PXR as a heterodimer with the 9-ci s retinoic acid receptor a (NR2B1). Taken together, these observations demo nstrate that the CYP2B6 gene is directly regulated by PXR and further estab lish this receptor as a key regulator of drug-metabolizing P450s.