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.
Goodwin
B
B
Department of Molecular Endocrinology, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
Moore
L B
LB
Stoltz
C M
CM
McKee
D D
DD
Kliewer
S A
SA
D020816:Amino Acid Motifs; D001189:Aryl Hydrocarbon Hydroxylases; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D019281:Dimerization; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating