Receptor-dependent regulation of the CYP3A4 gene

A CYP3A4 promoter-reporter gene construct has been used to assess the ability of 16 known (in vivo) and putative (in vitro) inducers to transactivate a CYP3A4 reporter gene in HepG2 cells. With the exception of pravastatin, the remaining 15 compounds transactivated the CYP3A4 reporter gene with differing inductive abilities (I-max:EC50) over two orders of magnitude, ranging from 1.1 (phenytoin) to 222.9 (lovastatin) in a receptor-supplemented system and it is proposed that the lack of response to pravastatin is due to loss of the known hepatic uptake transporter in HepG2 cells. In addition, reporter gene assays were used to investigate two promoter mutants namely a T to C change at -191 bp in the hepatic nuclear factor 3 binding site (HNF-3, - 187 to - 194 bp) and an A to G change at - 205 bp in the oestrogen response element (ERE, - 202 to - 212 bp), which conferred differential responsiveness to steroid and xenobiotic inducers. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.