TY - JOUR T1 - Involvement of Glucocorticoid Receptor and Pregnane X Receptor in the Regulation of Mouse CYP3A44 Female-Predominant Expression by Glucocorticoid Hormone JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1880 LP - 1885 DO - 10.1124/dmd.107.016832 VL - 35 IS - 10 AU - Wattanaporn Bhadhprasit AU - Tsutomu Sakuma AU - Nobuyuki Hatakeyama AU - Masahiro Fuwa AU - Kaori Kitajima AU - Nobuo Nemoto Y1 - 2007/10/01 UR - http://dmd.aspetjournals.org/content/35/10/1880.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -