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Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis

Yonggong Zhai1, Harish V Pai, Jie Zhou

  • 1Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

Molecular Endocrinology (Baltimore, Md.)
|September 16, 2006
PubMed

Insights

The pregnane X receptor (PXR) regulates steroid hormones, impacting adrenal steroid homeostasis. PXR activation disrupts corticosterone and aldosterone levels, affecting stress responses and potentially causing pseudo-Cushing

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Pharmacology

Background:

  • The pregnane X receptor (PXR) is known as a xenobiotic receptor controlling responses to foreign compounds.
  • Its role in endogenous metabolic regulation, particularly steroid homeostasis, remains less understood.

Purpose of the Study:

  • To investigate the endobiotic function of PXR in adrenal steroid homeostasis.
  • To determine the impact of PXR activation on glucocorticoid and mineralocorticoid levels and adrenal function.

Main Methods:

  • Utilized PXR-activating transgenic mouse models and pharmacological activation with rifampicin.
  • Measured plasma concentrations of corticosterone and aldosterone.
  • Assessed the activity of key adrenal steroidogenic enzymes (CYP11a1, CYP11b1, CYP11b2, 3beta-HSD).
  • Evaluated adrenal gland morphology, glucocorticoid circadian rhythm, and stress responses.

Main Results:

  • PXR activation, via genetic or pharmacological means, significantly increased plasma corticosterone and aldosterone levels.
  • Increased steroid levels correlated with enhanced activity of steroidogenic enzymes and adrenal cortex hypertrophy.
  • PXR activation led to loss of glucocorticoid circadian rhythm and blunted stress responses, despite a functional hypothalamus-pituitary-adrenal axis.
  • ACTH secretion and dexamethasone suppression remained normal, indicating ACTH-independent hypercortisolism.

Conclusions:

  • PXR plays a critical endobiotic role in maintaining adrenal steroid homeostasis.
  • PXR activation disrupts normal steroid production, leading to conditions resembling pseudo-Cushing's syndrome.
  • PXR is identified as a potential endocrine-disrupting factor with implications for steroid metabolism and drug-hormone interactions.

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