Inhibition of CYP1A1 by pharmaceutical drugs, omeprazol and ketoconazole as a mechanism for activation of aryl hydrocarbon receptor (AHR)

Abstract

Omeprazole (OMP) and ketoconazole (KTZ) have been shown to activate the AHR signaling pathway in spite of the fact that they bind to the receptor with low or no affinity. The aim of this study was to investigate whether KTZ and OMP can act as indirect activator of AHR. In order to evaluate the effects of KTZ and OMP on AHR signaling, we measured cytochromes p450 (CYP1A1) enzyme activity by ethoxyresorufin-O-deethylase (EROD) assay as endpoint. FICZ, at 1nM concentration, caused a transient elevation in the catalytic activity of CYP 1A1. KTZ and OMP were found to be inducer of CYP1A1 at concentrations above 50 µM. At early time of incubation (3hr), a dose-dependent inhibition of FICZ-induced EROD activity was seen. When OMP or KTZ were added together with FICZ, a prolonged activation of CYP1A1 was observed at later time of incubation (24h). Taken together, our findings support the earlier observation that we shown that CYP 1A1 inhibitors can act as an AHR activator though inhibition of metabolic degradation of FICZ.