Mechanisms of CYP3A Induction During Pregnancy: Studies in HepaRG Cells

AbstractActivity of CYP3A, an enzyme responsible for metabolism of many marketed drugs, is induced by ~  2-fold in pregnant women. Through studies in sandwich-cultured human hepatocytes (SCHH) and HepaRG cells, our laboratory has shown that this induction is likely mediated by the increase in cortisol plasma concentrations during pregnancy. Cortisol, at plasma concentrations observed during the thir d trimester (~ 800 nM), either alone or in combination with other pregnancy-related hormones, induces CYP3A activity in SCHH and HepaRG cells when cultured in dexamethasone-free media. To determine the mechanism(s) by which cortisol induces CYP3A activity, HepaRG cells were pre-incubated in dexam ethasone-free medium and then incubated for 72 h with cortisol (798 nM). Glucocorticoid receptor (GR), pregnane X receptor (PXR), and CYP3A4 or CYP3A5 were knocked down using siRNA, and mRNA expression of these genes was measured. CYP3A4, and not CYP3A5, was found to be the dominant contributor to total CYP3A activity in control- and cortisol-treated HepaRG cells. Constitutive mRNA expression of CYP3A4 in HepaRG cells was regulated by both PXR and GR whereas constitutive expression of CYP3A5 in HepaRG cells was regulated by GR alone. Cortisol-mediated CYP3A4 induction in HepaRG cells was pri marily mediated by GR-dependent PXR induction pathway and to a smaller extent via a PXR-independent pathway. Cortisol-mediated CYP3A5 induction was regulated by GR-dependent PXR-independent pat...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research