Estrogens and antiestrogens activate hPXR.
The pregnane X receptor (PXR, NR1I2) and the estrogen receptors (ERalpha, NR3A1 and ERbeta, NR3A2) bind a large number of compounds, including environmental pollutants and drugs, which exhibit remarkably diverse structural features. This prompted us to investigate if ER ligands could be PXR activators. We focused our attention on known estrogens from various chemical classes: physiological and synthetic estrogens and antiestrogens, plant and fungus estrogens, and other man-made chemicals belonging to phthalate plasticizers, surfactant-derived alkylphenols and cosmetics. Altogether, nearly 50 compounds were thus analyzed for their ability to activate human PXR in stably transfected cells, HGPXR cells, derived from HeLa cells and expressing luciferase under the control of a chimeric hPXR. Some of the newly identified hPXR activators were also checked for their ability to induce cytochrome P450 3A4 and 2B6 expressions in a primary culture of human hepatocytes. A significant proportion (54%) of compounds with estrogenic activity or able to bind ER were found to be hPXR activators: in particular, antiestrogens, mycoestrogens and phthalates. An even greater proportion is observed if estrogenic pesticides are included. Altogether, these results raise the question of the meaning and consequences of compounds with double PXR/ER activation ability.
Mnif
Wissem
W
INSERM U824, Montpellier, F-34298, Univ Montpellier 1, Montpellier F-34060, France.
Pascussi
Jean-Marc
JM
Pillon
Arnaud
A
Escande
Aurélie
A
Bartegi
Aghleb
A
Nicolas
Jean-Claude
JC
Cavaillès
Vincent
V
Duchesne
Marie-Josèphe
MJ
Balaguer
Patrick
P
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D002460:Cell Line; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D045166:Estradiol Congeners / Q000633:toxicity; D020847:Estrogen Receptor Modulators / Q000633:toxicity*; D004967:Estrogens / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D048789:Phytoestrogens / Q000633:toxicity; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*; D014162:Transfection
D045166:Estradiol Congeners; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D008024:Ligands; C000625852:NR1I2 protein, human; D048789:Phytoestrogens; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating