Journal article
Activation of a tunicate (Ciona intestinalis) xenobiotic receptor orthologue by both natural toxins and synthetic toxicants
Toxicon (Oxford), Vol.59(2), pp.365-372
02/2012
DOI: 10.1016/j.toxicon.2011.12.008
PMID: 22206814
Abstract
Vertebrate xenobiotic receptors are ligand-activated nuclear receptors (NRs) that bind exogenous biologically active chemicals before activating the transcription of genes involved in xenobiotic metabolism and excretion. Typically, xenobiotic receptors have ligand binding domains (LBDs) that can accommodate a structurally diverse array of molecules and in addition display high levels of inter-taxa sequence diversity suggestive of positive selection. Pursuing the idea that xenobiotic receptors may adaptively evolve to bind toxic chemicals commonly present in an organism's environment/diet, we examined ligand binding by a xenobiotic receptor orthologue of a marine filter-feeding organism. The solitary tunicate Ciona intestinalis (Phylum Chordata) genome encodes an orthologue of the vertebrate pregnane X receptor (PXR) and vitamin D receptor (VDR), here denoted CiVDR/PXRα. In a luciferase reporter assay the CiVDR/PXRα was activated, at nanomolar concentrations, by two of four natural marine microalgal biotoxins tested (okadaic acid, EC50 = 18.2 ± 0.9 nM and pectenotoxin-2, EC50 = 37.0 ± 3.5 nM) along with 1 of 11 synthetic toxicants (esfenvalerate: EC50 = 0.59 ± 0.7 μM). Two related C. intestinalis NRs, orthologous to vertebrate farnesoid X receptor and liver X receptors, respectively, along with the PXR of a freshwater fish (zebrafish, Danio rerio), were not activated by any of the 15 chemicals tested. In contrast, human PXR was activated by okadaic acid at similar concentrations to CiVDR/PXRα (EC50 = 7.2 ± 1.1 nM) but not by pectenotoxin-2. A common features pharmacophore developed for the CiVDR/PXRα ligand consisted of an off-center hydrogen bond acceptor flanked by two hydrophobic regions. The results of this study are consistent with the original hypothesis that natural toxins, present in the diet of filter-feeding marine invertebrates, may have acted as selective agents in the molecular evolution of tunicate xenobiotic receptors. Bioassays based on tunicate xenobiotic receptor activation may find application in marine environmental monitoring and bioprospecting.
► A tunicate xenobiotic receptor activated by two natural microalgal biotoxins. ► Natural marine toxins may act as selective agents in xenobiotic receptor evolution. ► Xenobiotic receptors may provide ‘sensor elements’ for monitoring and bioprospecting.
Details
- Title: Subtitle
- Activation of a tunicate (Ciona intestinalis) xenobiotic receptor orthologue by both natural toxins and synthetic toxicants
- Creators
- Andrew E Fidler - Cawthron Institute, Private Bag 2, Nelson 7012, New ZealandPatrick T Holland - Cawthron Institute, Private Bag 2, Nelson 7012, New ZealandErica J Reschly - Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USASean Ekins - Collaborations in Chemistry, Fuquay-Varina, NC 27526, USAMatthew D Krasowski - Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Resource Type
- Journal article
- Publication Details
- Toxicon (Oxford), Vol.59(2), pp.365-372
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.toxicon.2011.12.008
- PMID
- 22206814
- ISSN
- 0041-0101
- eISSN
- 1879-3150
- Grant note
- name: United States of America National Institutes of Health, award: K08-GM074238; DOI: 10.13039/501100001506, name: New Zealand Ministry of Science and Innovation, award: CAWX1001
- Language
- English
- Date published
- 02/2012
- Academic Unit
- Pathology
- Record Identifier
- 9984046934402771
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