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.

Role of vitamin D receptor in the regulation of CYP3A gene expression

“…For the induction of CYP3A5 , some studies mentioned the involvement of GR, PXR and CAR in the liver and intestine 65 . Others pointed out that neither its basal expression in extrahepatic tissues was dependent on PXR, nor its transcription was responsive to PXR ligands 66 . Neither the hepatic nor intestinal CYP3A5 genes were sensitive to VDR ligands (discussed in next sections).…”

C2H2-Type Zinc Finger Proteins: Evolutionarily Old and New Partners of the Nuclear Hormone Receptors

“…101 YY1 cooperates with PXR for the regulation of the cytochrome P450 enzymes involved in xenobiotic metabolism, such as CYP3A4 and CYP3A5. 102 YY1 represses the transcriptional activity of VDR on vitamin D-responsive genes in osteoblastic cells. 149 In renal cells, it represses VDR-mediated transcription of the 24(OH) gene whose encoding enzyme inactivates vitamin D (25-dihydroxyvitamin D 3 ).…”

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

“…A YY1-binding site, which overlaps the PXR-binding site, is absent in the promoter region of CYP3A5 but is present in that of CYP3A4 . Binding of YY1 to this site on CYP3A4 represses its transcription [140]. Nem et al .…”