cytoplasm by chaperone proteins, such as HSP90, in order to keep its
transcriptional activity at constitutive levels. Translocation of CAR to the
nucleus is thought to be initiated by direct agonist binding to the receptor,
or through a partially elucidated ligand-independent mechanism involving
kinases that dephosphorylate CAR. Phenobarbital is an example of a drug
that does not bind to CAR, yet causes nuclear translocation and transcriptional
activation of a target gene, CYP2B6 (Qatanani and Moore, 2005). From this
point, CAR dimerizes with RXR and other transcription factors, binds to its
respective RE in the promoter region of target genes and initiates transcription.
Activation of AhR target genes can also occur through two distinct
mechanisms. The inactive AhR resides in the cytoplasm in a complex with
HSP90 and other proteins. The receptor can be activated upon ligand binding
(ligands such as TCDD, 3MC, BNF) and translocates to the nucleus where it
dimerizes with the AhR nuclear translocator. This dimer complex recruits
additional transcription factors and binds to the promoter region of AhR
target gene response elements and initiates transcription. Another mechanism
by which AhR target genes can be activated is through a ligand-independent
mechanism involving protein tyrosine kinases. Omeprazole-mediated induction
of CYP1A is thought to proceed through this particular signal transduction
pathway (Backlund and Ingelman-Sundberg, 2005).
FIGURE 5.3 Mechanism of PXR ligand activated induction of CYP3A4.124 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS