Phenobarbital is a classic inducer of cytochrome P450 enzymes. Through which nuclear receptor does phenobarbital-mediated CYP3A4/CYP2B6 induction primarily occur?
- A AhR (aryl hydrocarbon receptor) — a ligand-activated transcription factor in the cytosol
- B CAR (constitutive androstane receptor) — phenobarbital indirectly activates CAR, which heterodimerises with RXR to drive CYP expression ✓
- C PXR (pregnane X receptor) — the primary receptor for all drug-mediated CYP induction
- D PPAR-alpha (peroxisome proliferator-activated receptor) — mediates fibrate-induced CYP4A induction
Explanation
Phenobarbital induces CYP2B6 and CYP3A4 primarily through the Constitutive Androstane Receptor (CAR). Interestingly, phenobarbital does not directly bind CAR; instead it indirectly promotes CAR nuclear translocation by inhibiting its cytoplasmic anchoring via RACK1/protein phosphatase 2A. Nuclear CAR heterodimerises with RXR and binds phenobarbital response elements (PBRem) in CYP gene promoters. AhR mediates induction of CYP1A1/1A2 by polycyclic aromatic hydrocarbons. PXR mediates induction by rifampicin and St. John's Wort (CYP3A4). PPAR-alpha mediates fatty acid-responsive CYP4A induction.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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