Functioning of pregnan X receptor under conditions of nitrosative stress

Abstract

Pregnan X receptor (PXR) is a nuclear receptor that plays an important role in the regulation of the expression of biotransformation and metabolic enzymes. The functioning and possible mechanisms of PXR regulation under conditions of nitrosative stress have not been studied, which served as the purpose of this study. The work was performed on Caco-2 cells. Nitrosative stress (NS) was modeled using S-nitrosoglutathione (GSNO) at concentrations of 1 μM, 10 μM, 50 μM, 100 μM, and 500 μM and incubation during of 3 h, 24 h, and 72 h. The amount of PXR was assessed byWestern blotting. Incubation of Caco-2 cells with all concentrations GSNO for 3 h led to a decrease in the amount of PXR. Incubation with GSNO (1-50 μM) for 24 h was accompanied by an increase in the amount of PXR, while at a concentration of 100 μM this indicator did not significantly differ from the control, at a concentration of 500 μM it was lower. Prolonged incubation (72 h) enhanced NS and led to a normalization (1 μM GSNO) or a decrease of the PXR level (10-500 μM GSNO). The induction of PXR by GSNO was mediated by the effect of the nitrosative stress product bityrosine on the transcription factor. It was shown that bityrosine at concentrations of 0,4 mM and 1 mM increased the amount of PXR.