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1. PLoS One. 2012;7(1):e30895. Epub 2012 Jan 23.

Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue
Expression and Induction of CYP3A5 and CYP3A4.

Nem D, Baranyai D, Qiu H, Gödtel-Armbrust U, Nestler S, Wojnowski L.

Department of Pharmacology, University Medical Center, Johannes Gutenberg
University Mainz, Mainz, Germany.

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.

PMCID: PMC3264657
PMID: 22292071 [PubMed - in process]