Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Abstract

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.

Pharmacokinetics of Marbofloxacin Following Oral Administration in Piperine, Quercetin Alone and Both in Combination Pretreated Broiler Chickens

“…Nuclear pregnane X receptor (PXR) is an important transcriptional regulator factor which controls the expression of drug transporter MDR1 and drug metabolizing enzyme CYP3A4 and regulates the drug clearance in the liver and intestine (Tebbens et al, 2018). After piperine and quercetin combined treatment, drug metabolizing enzyme CYP3A37 and drug efflux protein MDR1 mRNA expressions were significantly (p < 0.05) down regulated in liver and duodenum as compared to normal chickens (Patel et al, 2019).…”

When special populations intersect with drug–drug interactions: Application of physiologically‐based pharmacokinetic modeling in pregnant populations

“…The simulation of raltegravir–rifampicin DDI in pregnancy performed here most likely represents a worst‐case scenario, as both rifampicin and the pregnancy hormone, progesterone, induce UGT1A1 via the transcription factor pregnane X receptor (PXR) (Gardner‐Stephen et al., 2004; Jeong et al., 2008; Sugatani et al., 2005). There is also evidence that PXR downregulates its own expression (Bailey et al., 2011; Tebbens et al., 2018). It is possible that the extent of the combined induction caused by rifampicin and pregnancy is less than predicted either due to competitive binding of the two PXR ligands or via the negative feedback loop demonstrated by PXR.…”

Heat treatment functionalizes hepatocyte-like cells derived from human embryonic stem cells

“…It is possible that CYP3A4 activity is facilitated by a temperature dependent heat shock protein. Previous research has shown that HSP90 is involved in the CYP3A4 synthesis process as a molecular chaperone [16]. Furthermore, similar to the liver, skeletal muscle and brain tissue also produce heat.…”