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Open Access Highly Accessed Research article

Functional evolution of the vitamin D and pregnane X receptors

Erica J Reschly1, Afonso Celso Dias Bainy2, Jaco Joaquim Mattos2, Lee R Hagey3, Nathan Bahary4, Sripal R Mada5, Junhai Ou5, Raman Venkataramanan5 and Matthew D Krasowski1*

Author Affiliations

1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

2 Departamento de Bioquimica, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

3 Department of Medicine, University of California at San Diego, San Diego, CA, USA

4 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

5 Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA

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BMC Evolutionary Biology 2007, 7:222  doi:10.1186/1471-2148-7-222

Published: 12 November 2007

Abstract

Background

The vitamin D receptor (VDR) and pregnane X receptor (PXR) are nuclear hormone receptors of the NR1I subfamily that show contrasting patterns of cross-species variation. VDR and PXR are thought to have arisen from duplication of an ancestral gene, evident now as a single gene in the genome of the chordate invertebrate Ciona intestinalis (sea squirt). VDR genes have been detected in a wide range of vertebrates including jawless fish. To date, PXR genes have not been found in cartilaginous fish. In this study, the ligand selectivities of VDRs were compared in detail across a range of vertebrate species and compared with those of the Ciona VDR/PXR. In addition, several assays were used to search for evidence of PXR-mediated hepatic effects in three model non-mammalian species: sea lamprey (Petromyzon marinus), zebrafish (Danio rerio), and African clawed frog (Xenopus laevis).

Results

Human, mouse, frog, zebrafish, and lamprey VDRs were found to have similar ligand selectivities for vitamin D derivatives. In contrast, using cultured primary hepatocytes, only zebrafish showed evidence of PXR-mediated induction of enzyme expression, with increases in testosterone 6β-hydroxylation activity (a measure of cytochrome P450 3A activity in other species) and flurbiprofen 4-hydroxylation activity (measure of cytochrome P450 2C activity) following exposure to known PXR activators. A separate assay in vivo using zebrafish demonstrated increased hepatic transcription of another PXR target, multidrug resistance gene (ABCB5), following injection of the major zebrafish bile salt, 5α-cyprinol 27-sulfate. The PXR target function, testosterone hydroxylation, was detected in frog and sea lamprey primary hepatocytes, but was not inducible in these two species by a wide range of PXR activators in other animals. Analysis of the sea lamprey draft genome also did not show evidence of a PXR gene.

Conclusion

Our results show tight conservation of ligand selectivity of VDRs across vertebrate species from Agnatha to mammals. Using a functional approach, we demonstrate classic PXR-mediated effects in zebrafish, but not in sea lamprey or African clawed frog liver cells. Using a genomic approach, we failed to find evidence of a PXR gene in lamprey, suggesting that VDR may be the original NR1I gene.