Abstract
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 ratCYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate theCYP3A23 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.
Footnotes
- Received June 22, 1998.
- Accepted September 15, 1998.
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Send reprint requests to: Dr. Erin Schuetz, Dept. of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis TN 38105. E-mail: erin.schuetz{at}stjude.org
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This work was supported by National Institute of Health Research Grants ES08658 (E.G.S.), ES05851 (J.D.S.), P30-CA21765 (E.G.S., J.D.S.) and by the American Lebanese Syrian Associated Charities (ALSAC).
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1 CYP3A23 refers to the major dexamethasone, PCN and phenobarbital inducible form of CYP3A in rat liver (Komori and Oda, 1994) which is now recognized to be CYP3A23, not CYP3A1. TheCYP3A 5′flanking regulatory sequence previously identified as CYP3A1 (Burger et al., 1992; Quattrochi et al., 1995; Kliewer et al., 1998) is in fact CYP3A23 (Nelson et al., 1993; Barwick et al., 1996). Likewise, because the CYP3A1 cDNA probe used in all previous publications of CYP3A regulation cannot distinguish between CYP3A1 and CYP3A23, we refer to the CYP3A in these publications as CYP3A23.
- The American Society for Pharmacology and Experimental Therapeutics
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Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element
