title: Pregnane X receptor and yin yang 1 contribute to the differential tissue expression and induction of CYP3A5 and CYP3A4.
abstract: The hepato-intestinal induction of the detoxifying enzymes CYP3A4 and CYP3A5 by the xenosensing pregnane X receptor (PXR) constitutes a key adaptive response to oral drugs and dietary xenobiotics. In contrast to CYP3A4, CYP3A5 is additionally expressed in several, mostly steroidogenic organs, which creates potential for induction-driven disturbances of the steroid homeostasis. Using cell lines and mice transgenic for a CYP3A5 promoter we demonstrate that the CYP3A5 expression in these organs is non-inducible and independent from PXR. Instead, it is enabled by the loss of a suppressing yin yang 1 (YY1)-binding site from the CYP3A5 promoter which occurred in haplorrhine primates. This YY1 site is conserved in CYP3A4, but its inhibitory effect can be offset by PXR acting on response elements such as XREM. Taken together, the loss of YY1 binding site from promoters of the CYP3A5 gene lineage during primate evolution may have enabled the utilization of CYP3A5 both in the adaptive hepato-intestinal response to xenobiotics and as a constitutively expressed gene in other organs. Our results thus constitute a first description of uncoupling induction from constitutive expression for a major detoxifying enzyme. They also suggest an explanation for the considerable tissue expression differences between CYP3A5 and CYP3A4.
authors.affiliation: Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Dieudonné
authors.initials: D
authors.lastname: Nem
authors.forename: Dorothea
authors.initials: D
authors.lastname: Baranyai
authors.forename: Huan
authors.initials: H
authors.lastname: Qiu
authors.forename: Ute
authors.initials: U
authors.lastname: Gödtel-Armbrust
authors.forename: Sebastian
authors.initials: S
authors.lastname: Nestler
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017385:Sequence Homology; D014018:Tissue Distribution / Q000235:genetics; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D050986:YY1 Transcription Factor; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human