Investigation of the CYP2C9 Induction Profile in Human Hepatocytes by Combining Experimental and Modelling Approaches

Ales      Belic; Manna      Temesvari; Krisztina      Kohalmy; Radim      Vrzal; Zdenek      Dvorak; Damjana      Rozman; Katalin      Monostory

doi:10.2174/138920009790820147

Abstract

The goal of the present review is to characterise the induction profile of CYP2C9, a member of the cytochrome P450 superfamily. Since the mechanism of CYP2C9 induction is fairly complex, with parallel processes triggered by various inducers, an evaluation of the experimental results is often a great challenge. At least three nuclear receptors, the glucocrticoid receptor (GR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), are known to mediate the CYP2C9 gene induction in man. However, mathematical modelling and simulation can provide an appropriate tool for the interpretation of CYP2C9 regulatory mechanisms. As an example, we present modelling and simulation approaches of the CYP2C9 gene expression in human hepatocytes treated with wellknown CYP2C9 inducers: the steroid hormone precursor dehydroepiandrosterone (DHEA) and the synthetic glucocorticoid dexamethasone (DXM). The results of the analysis suggest that in addition to the potent function of GR and the further involvement of PXR and CAR activated by DXM or DHEA, an additional factor might play a role in CYP2C9 regulation by DHEA. The novel potential candidate for DHEA action in CYP2C9 induction is likely to be the estrogen receptor. Additionally, the balance of DHEA sulphation-desulphation processes should also be considered in any description of DHEA-induced CYP2C9 profiles.

Keywords: CYP2C9, estrogen receptor, dehydroepiandrosterone, dexamethasone, nuclear receptors, mathematical modelling, simulation, dynamical systems