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Drug Metabolism and Disposition Fast Forward
First published on July 19, 2007; DOI: 10.1124/dmd.107.016832

0090-9556/07/3510-1880-1885$20.00
DMD 35:1880-1885, 2007

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Involvement of Glucocorticoid Receptor and Pregnane X Receptor in the Regulation of Mouse CYP3A44 Female-Predominant Expression by Glucocorticoid Hormone

Wattanaporn Bhadhprasit, Tsutomu Sakuma, Nobuyuki Hatakeyama, Masahiro Fuwa, Kaori Kitajima, and Nobuo Nemoto

Department of Toxicology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan

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, 11ß-[4-dimethylamino] phenyl-17ß-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-{alpha} (RXR{alpha}) 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-RXR{alpha} complex, and, second, indirect activation of the Cyp3a44 gene through the induction of PXR gene expression by the GR pathway.

Address correspondence to: Dr. Nobuo Nemoto, Department of Toxicology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: nnemoto{at}pha.u-toyama.ac.jp




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T. Sakuma, W. Bhadhprasit, T. Hashita, and N. Nemoto
Synergism of Glucocorticoid Hormone with Growth Hormone for Female-Specific Mouse Cyp3a44 Gene Expression
Drug Metab. Dispos., May 1, 2008; 36(5): 878 - 884.
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