Abstract
The role of the 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, as 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, 11β-[4-dimethylamino] phenyl-17β-hydroxy-17-[1-propynyl]estra-4,9-diene-3-one (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 was increased by RU486. Treatment of GR expression plasmid-transfected hepatocytes with DEX concentration dependently enhanced the expression of PXR as well as CYP3A44 mRNAs. A synergistic effect of DEX at submicromolar concentrations and rifampicin is observed. Furthermore, transfection of PXR and retinoid X receptor-α (RXRα) 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 the Cyp3a44 gene by the PXR-RXRα complex, and, second, indirect activation of the Cyp3a44 gene through the induction of PXR gene expression by the GR pathway.
Footnotes
-
This work was partly supported by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sport, and Science and the Smoking Research Foundation.
-
doi:10.1124/dmd.107.016832.
-
ABBREVIATIONS: CAR, constitutive androstane receptor; PXR, pregnane X receptor; GR, glucocorticoid receptor; GRE, glucocorticoid responsive element; bp, base pairs; RXRα, retinoid X receptor-α; DEX, dexamethasone; RU486, 11β-[4-dimethylamino] phenyl-17β-hydroxy-17-[1-propynyl] estra-4,9-diene-3-one; RT, reverse-transcriptase; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate.
- Received May 24, 2007.
- Accepted July 18, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|