Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system

Abstract : 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.
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.umontpellier.fr/hal-02879901
Contributeur : Romain Roquelaure <>
Soumis le : mercredi 24 juin 2020 - 13:53:28
Dernière modification le : vendredi 26 juin 2020 - 16:23:01

Lien texte intégral

Identifiants

Citation

Géraldine Lemaire, Wissem Mnif, Jean-Marc Pascussi, Arnaud Pillon, Fanja Rabenoelina, et al.. Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system. Toxicological Sciences, Oxford University Press (OUP), 2006, 91 (2), pp.501-509. ⟨10.1093/toxsci/kfj173⟩. ⟨hal-02879901⟩

Partager

Métriques

Consultations de la notice

47