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Vol. 54, Issue 6, 1113-1117, December 1998
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee 38105
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.
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