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ToxSci Advance Access published online on March 24, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj173
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 30, 2006
Accepted March 22, 2006

In Vitro Toxicology

Identification of New Human PXR Ligands among Pesticides Using a Stable Reporter Cell System

Géraldine Lemaire 1 1, Wissem Mnif 2 1, Jean-Marc Pascussi 3, Arnaud Pillon 1, Fanja Rabenoelina 1, Hélène Fenet 4, Elena Gomez 4, Claude Casellas 4, Jean-Claude Nicolas 1, Vincent Cavaillès 1, Marie-Josèphe Duchesne 1, and Patrick Balaguer 1 *

1 Inserm, U540, Montpellier, F-34090 France; Univ Montpellier I, Montpellier, F-34000 France
2 Inserm, U540, Montpellier, F-34090 France; Univ Montpellier I, Montpellier, F-34000 France; Unité 02/UR/09-01, Monastir, 5019, Tunisia
3 Inserm, U632, Montpellier, F-34293, France
4 CNRS, UMR 5569, Montpellier, F-34293, France

* To whom correspondence should be addressed.
Patrick Balaguer, E-mail: balaguer{at}montp.inserm.fr


  Abstract

Pregnane X receptor (hPXR, NR1I2) is activated by various chemically unrelated compounds, including environmental pollutants and drugs. We proceeded here to in vitro screening of 28 pesticides with a new reporter system that detects hPXR activators. The cell line was obtained by a two-step stable transfection of cervical cancer HeLa cells. The first transfected cell line, HG5LN, contained an integrated luciferase reporter gene under the control of a GAL4 yeast transcription factor binding site. The second cell line, HGPXR, was derived from HG5LN and stably expressed hPXR ligand binding domain (LBD) fused to GAL4 DNA binding domain (DBD). The HG5LN cells were used as a control to detect non-specific activities. Pesticides from various chemical classes were demonstrated, for the first time, to be hPXR activators: i) herbicides: pretilachlor, metolachlor and alachlor chloracetanilides, oxadiazon oxyconazole, and isoproturon urea; ii) fungicides: bupirimate and fenarimol pyrimidines, propiconazole, fenbuconazole, prochloraz conazoles and imazalil triazole; and iii) insecticides: toxaphene organochlorine, permethrin pyrethroid, fipronil pyrazole, and diflubenzuron urea. Pretilachlor, metolachlor, bupirimate and oxadiazon had an affinity for hPXR equal to or greater than the positive control rifampicin. Some of the newly identified hPXR activators were also checked for their ability to induce cytochrome P450 3A4 (CYP3A4) expression in a primary culture of human hepatocytes. HGPXR, with HG5LN as a reference, was grafted onto nude mice to assess compound bioavailability through in vivo quantification of hPXR activation. Altogether, our data indicate that HGPXR cells are an efficient tool for identifying hPXR ligands and establishing pesticides as hPXR activators.

Keywords: pesticide; pregnane X receptor; luciferase reporter; HeLa cell; nude mouse; cytochrome P450 3A4.

1These authors contributed equally to the study.


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