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ToxSci Advance Access originally published online on March 24, 2006
Toxicological Sciences 2006 91(2):501-509; 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

Identification of New Human Pregnane X Receptor Ligands among Pesticides Using a Stable Reporter Cell System

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

* INSERM, U540, F-34090 Montpellier, France; {dagger} Université Montpellier I, F-34000 Montpellier, France; {ddagger} Unité 02/UR/09-01, Monastir 5019, Tunisia; § INSERM U632, F-34293 Montpellier, France; and CNRS, UMR 5569, F-34293 Montpellier, France

Received January 30, 2006; accepted March 22, 2006

Pregnane X receptor (PXR, 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 human pregnane X receptor (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 fused to GAL4 DNA-binding domain (DBD). The HG5LN cells were used as a control to detect nonspecific activities. Pesticides from various chemical classes were demonstrated, for the first time, to be hPXR activators: (1) herbicides: pretilachlor, metolachlor, and alachlor chloracetanilides, oxadiazon oxiconazole, and isoproturon urea; (2) fungicides: bupirimate and fenarimol pyrimidines, propiconazole, fenbuconazole, prochloraz conazoles, and imazalil triazole; and (3) 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 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.

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


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