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Vol. 29, Issue 10, 1325-1331, October 2001
Institut National de la Santé et de la Recherche
Médicale, Centre National de la Recherche Scientifique,
Montpellier, France (L.D., J.-M.P., E.A., P.M., M.-J.V); and Service de
Chirurgie, Hopital Saint Eloi, Montpellier, France (J.-M.F.)
The expression of three cytochromes P450 (CYP3A4, CYP2C9, and
CYP2B6) was investigated in primary human hepatocyte cultures following
treatment with four calcium channel modulators (CCM) of the
dihydropyridine family, three antagonists (nifedipine, nicardipine, and
isradipine), and one agonist (BK8644). Induction of CYP3A4 was studied
by Northern blot, Western blot, and enzymatic activity. Induction began
between 1 and 10 µM CCM and was dependent on the presence of
dexamethasone (100 nM) in the medium. CYP3A4 mRNA accumulation started
only after 16 h of treatment because pregnane X receptor (hPXR)
synthesis was needed. Cotransfection experiments showed that the
proximal and the distal PXR response elements of the CYP3A4 promoter
and hPXR (HepG2 cells) or dexamethasone-induced hPXR (primary
hepatocytes) were necessary to obtain full induction. Furthermore,
glutathione S-transferase pull-down assays
demonstrated that the CCM tested can act as hPXR ligands. In addition,
cotransfection experiments in CV1 cells showed that these compounds
failed to reverse CAR (constitutively activated receptor) inactivation
by androstenol. Finally, 10 µM CCM induced both CYP2C9 and CYP2B6, strengthening the evidence that hPXR is involved in the regulation of
these genes. All together, these results widen the field of hPXR
activators to a new class of ligand, namely the CCM of the dihydropyridine family.
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