Involvement of glucocorticoid receptor and pregnane X receptor in the regulation of mouse CYP3A44 female-predominant expression by glucocorticoid hormone
Involvement of glucocorticoid receptor and pregnane X receptor in the regulation of mouse CYP3A44 female-predominant expression by glucocorticoid hormone
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DOI：
10.1124/dmd.107.016832
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发表时间：
2007-10-01
影响因子：
3.9
通讯作者：
Nemoto, Nobuo
中科院分区：
文献类型：
--
作者：
Bhadhprasit, Wattanaporn;Sakuma, Tsutomu;Nemoto, Nobuo
糖皮质激素受体（GR）和妊娠X受体（PXR）在糖皮质激素调节小鼠CYP3A44雌性显性表达中的作用通过雌性小鼠肝细胞的原代培养进行了评估，因为在肾上腺切除的雌性小鼠中，CYP3A44的表达被抑制，通过地塞米松（DEX）治疗恢复，而在雄性小鼠肝脏中未检测到。选择糖皮质激素（如DEX、氢化可的松和皮质酮）、11 β -[4-二甲胺]苯基-17 β -羟基-17-[1-丙基]estra-4,9-二烯-3-one （RU486）、GR拮抗剂和PXR激动剂、利福平（PXR激动剂）来研究GR/PXR激活与Cyp3a44基因表达的关系。RU486没有抑制糖皮质激素诱导的CYP3A44的表达，反而增加了表达。用DEX浓度处理GR表达质粒转染的肝细胞，可依赖性地增强PXR和CYP3A44 mrna的表达。在亚微摩尔浓度下观察到DEX和利福平的协同效应。此外，DEX转染PXR和类视黄醇X受体α (RXR α)也能显著诱导CYP3A44 mRNA表达。这些结果表明，DEX在CYP3A44表达中起双重作用：一是通过PXR- rxr α复合物直接激活CYP3A44基因，二是通过GR途径诱导PXR基因表达间接激活CYP3A44基因。
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, 11 beta-[4-dimethylamino] phenyl-17 beta-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.