Functionally Conserved Xenobiotic Responsive Enhancer in Cytochrome P450 3A7

Nuclear receptors CAR and PXR play a key role in cytochrome P450 gene induction by xenobiotics. Human cytochrome P450 3A7 (CYP3A7) is expressed from early in gestation until the perinatal period, when there is a switch in expression to CYP3A4. Here we demonstrate that a PXR and CAR responsive enhanc...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2001-01, Vol.280 (1), p.139-144
Main Authors: Bertilsson, Göran, Berkenstam, Anders, Blomquist, Patrik
Format: Article
Language:English
Subjects:
Aryl Hydrocarbon Hydroxylases
Base Sequence
CAR
Conserved Sequence
CYP3A4
CYP3A7
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - biosynthesis
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Enhancer Elements, Genetic - drug effects
Enhancer Elements, Genetic - physiology
Enzyme Induction
Evolution, Molecular
Gene Expression Regulation, Enzymologic - drug effects
Genes, Reporter
Humans
Medicin och hälsovetenskap
Mixed Function Oxygenases - genetics
Molecular Sequence Data
NR1I2
NR1I3
nuclear receptor
PAR
Promoter Regions, Genetic
PXR
Recombinant Proteins - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sequence Deletion
SXR
Transcriptional Activation
Transfection
Tumor Cells, Cultured
xenobiotic response element module
Xenobiotics - pharmacology
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Summary:Nuclear receptors CAR and PXR play a key role in cytochrome P450 gene induction by xenobiotics. Human cytochrome P450 3A7 (CYP3A7) is expressed from early in gestation until the perinatal period, when there is a switch in expression to CYP3A4. Here we demonstrate that a PXR and CAR responsive enhancer is located approximately 8 kb upstream of the proximal CYP3A7 promoter. This distal xenobiotic responsive enhancer module (XREM) is conserved with the XREM of CYP3A4. Interestingly, not only the XREM, but also the entire promoters exhibit 90% sequence identity up to −8.8 kb, indicating a close evolutionary distance. We propose that the promoters have coevolved to functionally conserve P450 gene induction in response to xenobiotics through CAR and PXR. Thus, nuclear receptors for xenobiotics may not only play a role to provide a survival advantage during adulthood, but also to protect the embryo against endogenous and exogenous toxins.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2000.4066