Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds
Delfosse, V., Dendele, B., Huet, T., Grimaldi, M., Boulahtouf, A., Gerbal-Chaloin, S., Beucher, B., Roecklin, D., Muller, C., Rahmani, R., Cavaillès, V., Daujat-Chavanieu, M., Vivat, V., Pascussi, J-M., Balaguer, P. and Bourguet, W.
Notes: Humans are exposed to a cocktail of low-dose chemicals in the environment, through diet, and through medication. However, most studies looking at compound toxicity, look at these compounds in isolation, not as they might be encountered in the environment—in mixtures. The pregnane X receptor (PXR) is a xenoreceptor that has been identified by the US Environmental Protection Agency as a major target of environmental and dietary chemicals, and many studies have highlighted the role of nuclear receptors like PXR in transducing the deleterious effects of endocrine disrupting compounds in the environment. The authors of this study used compound screening and functional analysis to demonstrate that the combined use of an environmentally persistent organochlorine pesticide and the active component of contraceptive pills (17α-ethinylestradiol) produces synergistic effects on PXR and expression of its target gene, the cytochrome P450 gene, CYP34A. Gene expression of CYP3A4 was measured using a luciferase reporter created in a pGL3-basic backbone. Activity of the CYP3A4 protein was measured in primary human hepatocytes using the P450-Glo™ CYP3A4 Assay with Luciferin-IPA, and cell number was normalized using the CellTiter-Glo® Luminescent Cell Viability Assay. (4579)
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