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

Bryan Goodwin, Linda B. Moore, Catherine M. Stoltz, David D. McKee, Steven A. Kliewer

Research output: Contribution to journalArticle

343 Scopus citations

Abstract

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; NR112) and constitutive androstane receptor (CAR; NR113) 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 the CYP2B6 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 the CYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s.

Original languageEnglish (US)
Pages (from-to)427-431
Number of pages5
JournalMolecular Pharmacology
Volume60
Issue number3
StatePublished - Sep 4 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Goodwin, B., Moore, L. B., Stoltz, C. M., McKee, D. D., & Kliewer, S. A. (2001). Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Molecular Pharmacology, 60(3), 427-431.