The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals

Christoph Handschin¹^,2, Sharon Blättler¹, Adrian Roth¹, Renate Looser¹, Mikael Oscarson¹, Michel R Kaufmann¹, Michael Podvinec¹, Carmela Gnerre¹^,3 and Urs A Meyer¹

¹Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland

²(Present Address) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

³(Present Address) Actelion Pharmaceuticals Ltd., CH-4123 Allschwil, Switzerland

Nuclear Receptor 2004, 2:7doi:10.1186/1478-1336-2-7


Published:	12 October 2004

Abstract

Background

Drugs and other xenobiotics alter gene expression of cytochromes P450 (CYP) by activating the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in mammals. In non-mammalian species, only one xenosensor gene has been found. Using chicken as a model organism, the aim of our study was to elucidate whether non-mammalian species only have one or two xenosensors like mammals.

Results

To explore the evolutionary aspect of this divergence, we tried to identify additional xenobiotic sensing nuclear receptors in chicken using various experimental approaches. However, none of those revealed novel candidates. Ablation of chicken xenobiotic receptor (CXR) function by RNAi or dominant-negative alleles drastically reduced drug-induction in a chicken hepatoma cell line. Subsequently, we functionally and structurally characterized CXR and compared our results to PXR and CAR. Despite the high similarity in their amino acid sequence, PXR and CAR have very distinct modes of activation. Some aspects of CXR function, e.g. direct ligand activation and high promiscuity are very reminiscent of PXR. On the other hand, cellular localization studies revealed common characteristics of CXR and CAR in terms of cytoplasmic-nuclear distribution. Finally, CXR has unique properties regarding its regulation in comparison to PXR and CAR.

Conclusion

Our finding thus strongly suggest that CXR constitutes an ancestral gene which has evolved into PXR and CAR in mammals. Future studies should elucidate the reason for this divergence in mammalian versus non-mammalian species.