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 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.
Bertilsson
G
G
Department of Cell and Molecular Biology, Medical Nobel Institute, S-171 77 Stockholm, Sweden.
Berkenstam
A
A
Blomquist
P
P
D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D017124:Conserved Sequence; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000502:physiology*; D004790:Enzyme Induction; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D015262:Xenobiotics / Q000494:pharmacology*
D011994:Recombinant Proteins; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human