Received for publication May 29, 2007.
Revised July 16, 2007.
Accepted for publication July 18, 2007.

Involvement of glucocorticoid receptor and pregnane X receptor in the regulation of mouse CYP3A44 female-predominant expression by glucocorticoid hormone

Abstract

The role of glucocorticoid receptor (GR) and pregnane X receptor (PXR) in the regulation of female-predominant expression of mouse CYP3A44 by glucocorticoid hormones was evaluated using a primary culture of female mouse hepatocytes, since the expression was suppressed in adrenalectomized female mice, restored by dexamethasone (DEX) treatment, and was not detected in male mouse livers. Glucocorticoid hormones, such as DEX, hydrocortisone and corticosterone, RU486, antagonists for GR and an agonist for PXR, and rifampicin, an agonist for PXR were chosen to investigate the relationship of GR/PXR activation and Cyp3a44 gene expression. Glucocorticoid-inducible expression of CYP3A44 was not suppressed, but rather increased by RU486. Treatment of GR expression plasmid-transfected hepatocytes with DEX concentration-dependently enhanced the expression of PXR as well as CYP3A44 mRNAs. The synergistic effect of DEX at submicromolar concentration and rifampicin is observed. Furthermore, transfection of PXR and retinoid X receptor- (RXR) also showed prominent induction of CYP3A44 mRNA by DEX. These results suggest that DEX plays a dual role in CYP3A44 expression; first, direct activation of Cyp3a44 gene by PXR-RXR complex, and second, indirect activation of Cyp3a44 gene through the induction of PXR gene expression by the GR pathway.

Key words: CYP expression, CYP gene regulation, CYP3A, nuclear receptors, PXR

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