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Submitted on July 17, 2006
Accepted on September 7, 2006
1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
* To whom correspondence should be addressed. E-mail: wex6{at}pitt.edu.
The pregnane X receptor (PXR) was isolated as a "xenobiotic receptor" that regulates responses to various xenobiotic agents. In this study, we show that PXR plays an important endobiotic role in adrenal steroid homeostasis. Activation of PXR by genetic (transgene) or pharmacological (ligand, rifampicin) markedly increased plasma concentrations of corticosterone and aldosterone, the respective primary glucocorticoid and mineralocorticoid in rodents. The increased levels of corticosterone and aldosterone were associated with activation of adrenal steroidogenic enzymes, including CYP11a1, CYP11b1, CYP11b2 and 3
-Hsd. The PXR-activating transgenic mice also exhibited hypertrophy of the adrenal cortex, loss of glucocorticoid circadian rhythm, and lack of glucocorticoid responses to psychogenic stress. Interestingly, the transgenic mice had normal pituitary secretion of adrenocorticortropic hormone (ACTH) and the corticosterone suppressing effect of dexamethasone (DEX) was intact, suggesting a functional hypothalamus-pituitary-adrenal (HPA) axis despite a severe disruption of adrenal steroid homeostasis. The ACTH-independent hypercortisolism in the PXR-activating transgenic mice is reminescent of the pseudo-Cushing's syndrome in patients. The glucocorticoid effect appears to be PXR-specific, as the activation of constitutive androstane receptor (CAR) in transgenic mice had little effect. We propose that PXR is a potential endocrine disrupting factor that may have broad implications in steroid homeostasis and drug-hormone interactions.
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