Environmental xenobiotics and the antihormones cyproterone acetate and spironolactone use the nuclear hormone pregnenolone X receptor to activate the CYP3A23 hormone response element.
The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient co-transfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs.
Schuetz
E G
EG
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. erin.schuetz@stjude.org
Brimer
C
C
Schuetz
J D
JD
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017373:Cyproterone Acetate / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D004785:Environmental Pollutants / Q000494:pharmacology*; D004789:Enzyme Activation; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011284:Pregnenolone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D013552:Swine; D014158:Transcription, Genetic; D014162:Transfection; D015262:Xenobiotics / Q000494:pharmacology*
D000726:Androgen Antagonists; D004785:Environmental Pollutants; D000451:Mineralocorticoid Receptor Antagonists; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D013148:Spironolactone; D017373:Cyproterone Acetate; D011284:Pregnenolone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A