Speaker
Description
The nuclear receptor Pregnane X Receptor (PXR) is a key regulator of metabolic enzymes and transporters, characterized by complex dynamics essential for maintaining metabolic homeostasis. While PXR-mediated regulation is well-documented, the kinetic mechanisms governing its temporal oscillations remain poorly quantified [1,2]. This work introduces a mathematical model to investigate the circadian clock as the primary driver of PXR rhythmicity, demonstrating how rhythmic molecular inputs entrain these oscillations. Through analytical derivation, we quantify the influence of specific kinetic parameters associated with transcriptional regulation on temporal behavior, specifically regarding oscillatory amplitude and the phase delay of downstream enzymatic targets. Our findings provide a scalable predictive model across three levels: different nuclear receptors, specific Cytochrome P450 (CYP) isoforms, and drug-dependent interactions. These predictions suggest that amplified and shifted CYP oscillations may influence drug clearance profiles. This highlights a potential role for circadian timing in pharmacology and could provide a basis for exploring future personalized medicine strategies.
Bibliography
- RAY, D.W.: IN: CAMPBELL, M.J., BEVAN, C.L.: CIRCADIAN RHYTHM AND NUCLEAR RECEPTORS, springer, 143–153 (2022).
- LU, Y.-F., JIN, T., et al.: SEX DIFFERENCES IN THE CIRCADIAN VARIATION OF CYTOCHROME P450 GENES AND CORRESPONDING NUCLEAR RECEPTORS IN MOUSE LIVER. Chronobiology International 30(9), 1135–1143 (2013).
