Functioning of the Pregnan X Receptor under Oxidative Stress

Abstract

The pregnane X receptor (PXR) is a nuclear receptor that plays an important role in regulating the expression of biotransformation and metabolism enzymes, as well as transporter proteins. There are contradictory data in the literature on the effect of oxidative stress on the amount of PXR. The purpose of this study was to evaluate the effect of oxidative stress on the functioning of PXR. The work was performed on the Caco-2 cell line. Oxidative stress was modeled with hydrogen peroxide at concentrations of 0.1, 0.5, 1, 5, 10, 50, and 100 μM and incubation duration of 3, 24, and 72 h. The amount of PXR was estimated by Western blot method. H₂O₂ at all concentrations during incubation for 3 h did not significantly affect the amount of PXR. An increase in the exposure up to 24 h at prooxidant concentrations of 10, 50, and 100 μM led to an increase in the amount of PXR, which was combined with an increase in the content of lipid peroxidation products (LPPs). Continued exposure to hydrogen peroxide for up to 72 h was accompanied by an increase in the concentration of LPPs and a decrease in the amount of PXR to control values (at the H₂O₂ concentration of 10?μM) or below it (at H₂O₂ concentrations of 50 and 100 μM). Incubation of the cells with malonic dialdehyde, the final product of lipid peroxidation, at a concentration of 10 μM for 24 h led to an increase in the amount of PXR. Thus, exposure to hydrogen peroxide for 24 h led to an increase in the amount of PXR and was associated with the inducing effect of LPPs. An increase in the exposure to 72 h leveled this inducing effect.