Environmental xenobiotics and the antihormones cyproterone acetate and spironolactone use the nuclear hormone pregnenolone X receptor to activate theCYP3A23 hormone response element

The pregnenolone X receptor (PXR), a new member of the nuclear hormone rece ptor superfamily, was recently demonstrated to mediate glucocorticoid agoni st and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other ster oids and xenobiotics can up-regulate CYP3A23 expression, we determined whet her some of these other regulators used PXR to activate the CYP3A23 DR-3. T ransient cotransfection of LLC-PK1 cells with (CYP3A23)(2)-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chl ordane 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 antihorm ones of several steroid classes including the antimineralocorticoid spirono lactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and struc turally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activ ation of the (CYP3A23)(2)-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs.