Received for publication September 28, 2007.
Revised November 10, 2007.
Accepted for publication November 29, 2007.

Omeprazole stimulates the induction of human insulin-like growth factor binding protein-1 through Ah receptor activation

Abstract

Omeprazole (5-methoxy-2-{(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl}-3H-benzoimidazole), a benzoimidazole-derived gastric H⁺/K⁺-ATPase proton pump inhibitor (PPI) extensively prescribed for the treatment of gastro-esophageal acid reflux disease; can stimulate the expression of CYP1A1 via activation of the human aryl hydrocarbon receptor (hAhR) in an apparent non-ligand binding fashion. Here, we have examined the effect of non-classical i.e. non-ligand binding, AhR activation by omeprazole upon human insulin-like growth factor binding protein-1 (hIGFBP-1), a secreted phosphoprotein involved in regulation of IGF-I & II bioavailability and mitogenic activity. Analysis of the proximal promoter of the hIGFBP-1 gene reveals the presence of an AhR binding/dioxin response element (DRE). Quantitative mRNA analysis revealed hIGFBP-1 expression to be responsive to both ligand (TCDD) and non-ligand (omeprazole) modes of hAhR activation in the human hepatocarcinoma HepG2 cell line. Furthermore, mutagenesis of the DRE renders the hIGFBP-1 promoter unresponsive to both compounds in HepG2 cells. Similarly, siRNA-mediated hAhR ablation inhibits TCDD and omeprazole-dependent hIGFBP-1 induction, as determined by quantitative mRNA analysis. Co-treatment with cycloheximide further suggests a direct transcriptional role for hAhR at the hIGFBP-1 promoter. Omeprazole exposure prompted a significant increase in both hIGFBP-1 mRNA and secreted protein from HepG2 cells. Additionally, we present in vitro evidence indicating that omeprazole at a concentration comparable to that found circulating in subjects undergoing PPI therapy can stimulate the expression of hIGFBP-1. These data demonstrate that activation of hAhR by pharmaceuticals such as omeprazole can alter IGFBP-1 expression and thus may influence IGFBP-1 dependent physiological processes.

Key words: Ah receptor, Dioxin response element, HepG2, IGFBP-1, Transcription, omeprazole