Dexlansoprazole acts as a disruptor of the aryl hydrocarbon receptor and ITE.

Abstract

Dexlansoprazole, a proton pump inhibitor, is commonly used to treat gastro-oesophageal reflux disease and erosive esophagitis. The activated aryl hydrocarbon receptor (AhR) functions as a transcription factor by binding to the aryl hydrocarbon response element (AHRE) of its target genes, with cytochrome P450 (CYP) 1A1 being the most well-known target. In this study, we demonstrated that dexlansoprazole stimulates AhR activity, leading to increased CYP1A1 expression. Our findings indicate that treatment with 2 μM dexlansoprazole is sufficient to induce CYP1A1 mRNA and protein expression, as well as AHRE-mediated transcriptional activity, in both human and mouse cells. Using AhR signal-deficient mutant cells and specific AhR antagonists-SR1, GNF351, and CH-223191-we confirmed that AhR is required for dexlansoprazole-induced CYP1A1 expression. Additionally, we showed that dexlansoprazole promotes AhR nuclear translocation, acting as an AhR agonist. However, due to its lower potency compared to FICZ and ITE in activating AhR, dexlansoprazole suppresses FICZ- and ITE-induced CYP1A1 expression in human liver HepG2 and ovarian granulosa HO23 cell lines, suggesting that it functions as both an AhR agonist and a modulator. This study offers valuable insights into the potential clinical side effects of dexlansoprazole.