Department of Mathematics, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA.
Bull Math Biol. 2010 Oct;72(7):1799-819. doi: 10.1007/s11538-010-9508-5. Epub 2010 Feb 12.
The pregnane X receptor plays an integral role in the regulation of hepatic metabolism. It has been shown to regulate CYP3A4, which is the most abundant cytochrome P450 in the human liver. With its large and flexible ligand-binding domain, PXR can be activated by an enormous range of relatively small, hydrophobic, exogenous compounds. Upon activation, PXR partners with the retinoid X receptor (RXR) to form a heterodimer. The newly formed heterodimer binds to an appropriate DNA response element, causing increased transcription. This leads to an induction in the level of CYP3A4. These mechanistic steps are included into a biologically-based mathematical model. The quantitative model predicts fold level inductions of CYP3A4 mRNA and protein in response to PXR activation. Model parameter values have been taken from literature when appropriate. Unknown parameter values are estimated by optimizing the model results to published in vivo and in vitro data sets. A sensitivity analysis is performed to evaluate the model structure and identify future data needs which would be critical to revising the model.
pregnane X 受体在肝脏代谢的调节中起着重要作用。它被证明可以调节 CYP3A4，CYP3A4 是人类肝脏中最丰富的细胞色素 P450。由于其庞大而灵活的配体结合域，PXR 可以被大量相对较小、疏水性的外源性化合物激活。激活后，PXR 与视黄酸 X 受体 (RXR) 形成异二聚体。新形成的异二聚体与适当的 DNA 反应元件结合，导致转录增加。这导致 CYP3A4 水平的诱导。这些机制步骤被包含在一个基于生物学的数学模型中。该定量模型预测了 PXR 激活后 CYP3A4 mRNA 和蛋白质的倍数诱导。在适当的情况下，从文献中获取模型参数值。通过优化模型结果来估计未知的参数值，以与已发表的体内和体外数据集相匹配。进行敏感性分析以评估模型结构，并确定对修改模型至关重要的未来数据需求。
