RT Journal Article SR Electronic T1 Regulation of the Human CYP2B6 Gene by the Nuclear Pregnane X Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 427 OP 431 VO 60 IS 3 A1 Bryan Goodwin A1 Linda B. Moore A1 Catherine M. Stoltz A1 David D. McKee A1 Steven A. Kliewer YR 2001 UL http://molpharm.aspetjournals.org/content/60/3/427.abstract AB Cytochromes P450 (P450s) are involved in the oxidative metabolism of a plethora 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 implicated in this phenomenon. In the present study, we examined the transcriptional 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 (PBREM) region of theCYP2B6 gene, a 51-base-pair enhancer element that mediates induction of CYP2B6 expression by CAR. The two nuclear receptor-binding motifs within the PBREM effectively bound PXR as a heterodimer with the 9-cis retinoic acid receptor α (NR2B1). Taken together, these observations demonstrate that theCYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s. The American Society for Pharmacology and Experimental Therapeutics