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

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 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 alpha (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.

[1]  J. Pascussi,et al.  Induction of CYP2C genes in human hepatocytes in primary culture. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[2]  L. Lesko,et al.  Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[3]  D W Nebert,et al.  P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. , 1996, Pharmacogenetics.

[4]  T. Willson,et al.  The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Moore,et al.  Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR* , 1997, The Journal of Biological Chemistry.

[6]  A. Anderson,et al.  Localization of a phenobarbital-responsive element (PBRE) in the 5'-flanking region of the rat CYP2B2 gene. , 1995, Gene.

[7]  S. Ekins,et al.  The role of CYP2B6 in human xenobiotic metabolism. , 1999, Drug metabolism reviews.

[8]  M. Denison,et al.  Xenobiotic-inducible Transcription of Cytochrome P450 Genes (*) , 1995, The Journal of Biological Chemistry.

[9]  L. Moore,et al.  Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands* , 2000, The Journal of Biological Chemistry.

[10]  T. Kawamoto,et al.  Phenobarbital-Responsive Nuclear Translocation of the Receptor CAR in Induction of the CYP2B Gene , 1999, Molecular and Cellular Biology.

[11]  D. Waxman,et al.  P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. , 1999, Archives of biochemistry and biophysics.

[12]  R Ohlsson,et al.  Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  B. Neuschwander‐Tetri,et al.  Humanized xenobiotic response in mice expressing nuclear receptor SXR , 2000, Nature.

[14]  B. Goodwin,et al.  The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. , 1999, Molecular pharmacology.

[15]  J. Lehmann,et al.  An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway , 1998, Cell.

[16]  T. Sueyoshi,et al.  The Nuclear Orphan Receptor CAR-Retinoid X Receptor Heterodimer Activates the Phenobarbital-Responsive Enhancer Module of the CYP2B Gene , 1998, Molecular and Cellular Biology.

[17]  J. Lehmann,et al.  The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. , 1998, The Journal of clinical investigation.

[18]  S. Safe,et al.  Reciprocal Activation of Xenobiotic Response Genes by Nuclear Receptors Sxr/pxr and Car , 2000 .

[19]  I. Phillips,et al.  Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics* , 2001, The Journal of Biological Chemistry.

[20]  D. Waxman,et al.  Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. , 1997, Cancer research.

[21]  D. Moore,et al.  A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements , 1994, Molecular and cellular biology.

[22]  S. Strom,et al.  Use of human hepatocytes to study P450 gene induction. , 1996, Methods in enzymology.

[23]  L. Moore,et al.  St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Oliver Burk,et al.  Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin* , 2001, The Journal of Biological Chemistry.

[25]  D. Moore,et al.  The Xenobiotic Compound 1,4-Bis[2-(3,5-Dichloropyridyloxy)]Benzene Is an Agonist Ligand for the Nuclear Receptor CAR , 2000, Molecular and Cellular Biology.

[26]  L. Moore,et al.  The Pregnane X Receptor: A Promiscuous Xenobiotic Receptor That Has Diverged during Evolution , 2000 .

[27]  Paavo Honkakoski,et al.  The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene* , 1999, The Journal of Biological Chemistry.

[28]  David D. Moore,et al.  Androstane metabolites bind to and deactivate the nuclear receptor CAR-β , 1998, Nature.

[29]  D. Moore,et al.  The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism , 2000, Nature.

[30]  W. Sabbagh,et al.  SXR, a novel steroid and xenobiotic-sensing nuclear receptor. , 1998, Genes & development.

[31]  P. Beaune,et al.  Human CYP2B6: expression, inducibility and catalytic activities. , 1999, Pharmacogenetics.