Receptor-dependent regulation of the CYP3A4 gene

• Published in: Toxicology (Amsterdam) Vol. 181; pp. 199 - 202
• Main Authors: Gibson, G.Gordon, El-Sankary, Wafaa, Plant, Nick J
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier Ireland Ltd 27-12-2002; Amsterdam Elsevier Science
• Subjects: Biological and medical sciences; Cell receptors; Cell structures and functions; Cells, Cultured; CYP3A4; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Dexamethasone; Enzyme Induction - drug effects; Estradiol - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - physiology; Genes, Reporter - genetics; Glucocorticoid receptor; Humans; Hydrocortisone; Hydrocortisone - pharmacology; Inducer ranking; Miscellaneous; Molecular and cellular biology; Mutation - genetics; Pregnane X Receptor; Promoter mutations; Promoter–reporter gene constructs; Receptor regulation; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - physiology; Receptors, Steroid - genetics; Receptors, Steroid - physiology; Rifampicin; Transcriptional activation; Transfection; β-estradiol; Dexamethasone; Inducer ranking; Promoter–reporter gene constructs; Cytochrome P450; Pregnane X receptor; CYP3A4; Hydrocortisone; β-estradiol; Receptor regulation; Rifampicin; Transcriptional activation; Glucocorticoid receptor; Promoter mutations; Transcription; Activation; Promoter; Regulation(control); Reporter gene; Gene; Promoter-reporter gene constructs
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(02)00281-0

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:EC
50) 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.