Department of Biophysics and Physical Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Kralove, Czech Republic.
Department of Applied Mathematics, Faculty of Mathematics and Computer Sciences, Mathematikon, University Heidelberg, Im Neuenheimer Feld 205, D-69120 Heidelberg, Germany.
Int J Mol Sci. 2018 Jun 15;19(6):1785. doi: 10.3390/ijms19061785.
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug⁻drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.
妊娠相关 X 受体 (PXR) 是一种药物/外源化学物质激活的转录因子，对于肝脏和肠道中主要细胞色素 P450 外源化学物质代谢酶 (CYP) 的表达和调节至关重要。PXR 调节的主要靶基因之一是细胞色素 P450 酶 (CYP3A4)，它是最重要的人类药物代谢酶。此外，PXR 被认为参与许多其他 CYP 的基础和/或诱导表达，如 CYP2B6、CYP2C8、2C9 和 2C19、CYP3A5、CYP3A7 和 CYP2A6。有趣的是，PXR 介导的靶基因调节的动力学尚未系统研究，我们只有少数描述细胞模型中 PXR 激活后基因表达动力学的机制数学和基于生物学的模型。此外，基于药物⁻药物相互作用或激素串扰的房室模型，已经建立了少数用于预测体内 CYP3A 代谢活性的间接数学 PKPD 模型。重要的是，已经描述了 PXR 调节中的几个负反馈回路。尽管当前的数学模型提出了这些自适应机制，但仍然缺乏基于足够实验数据的综合数学模型。在当前的综述中，我们总结和比较了这些模型，并讨论了一些应该考虑的问题，以便改进 PXR 介导的基因调节建模，并更好地理解 CYP 表达的定量和空间动力学。
