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; 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.
Footnotes
- Abbreviations:
- P450
- cytochrome P450, PXR
- pregnane X receptor
- CAR
- constitutive androstane receptor
- RXRα
- 9-cis retinoic acid receptor α
- DRn
- direct repeat with n-bp spacer
- bp, base pair(s)
- ER6
- everted repeat with 6-base-pair spacer
- PB
- phenobarbital
- PBRU
- phenobarbital-responsive unit
- PBREM
- phenobarbital-responsive enhancer module
- FBS
- fetal bovine serum
- DMSO
- dimethyl sulfoxide
- SPAP
- secreted placental alkaline phosphatase
- EMSA
- electrophoretic mobility-shift assay
- Received April 18, 2001.
- Accepted June 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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