PMID- 18055878 OWN - NLM STAT- MEDLINE DCOM- 20080324 LR - 20211020 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 324 IP - 3 DP - 2008 Mar TI - Omeprazole stimulates the induction of human insulin-like growth factor binding protein-1 through aryl hydrocarbon receptor activation. PG - 1102-10 AB - 5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl-3H-benzoimidazole (omeprazole), a benzoimidazole-derived gastric H(+)/K(+)-ATPase proton pump inhibitor (PPI) extensively prescribed for the treatment of gastroesophageal acid reflux disease, can stimulate the expression of CYP1A1 via activation of the human aryl hydrocarbon receptor (hAhR) in an apparent nonligand-binding manner. Here, we have examined the effect of nonclassical, i.e., nonligand binding, AhR activation by omeprazole upon human insulin-like growth factor binding protein (hIGFBP)-1, a secreted phosphoprotein involved in regulation of insulin-like growth factor-I/II bioavailability and mitogenic activity. Analysis of the proximal promoter of the hIGFBP-1 gene reveals the presence of an aryl hydrocarbon binding/dioxin response element (DRE). Quantitative mRNA analysis revealed hIGFBP-1 expression to be responsive to both ligand (TCDD) and nonligand (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. Likewise, small interfering RNA-mediated hAhR ablation inhibits TCDD and omeprazole-dependent hIGFBP-1 induction, as determined by quantitative mRNA analysis. Cotreatment 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. In addition, we present in vitro evidence indicating that omeprazole at a concentration comparable with 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. FAU - Murray, Iain A AU - Murray IA AD - Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 309A Life Sciences Bldg., The Pennsylvania State University, University Park, PA 16802, USA. FAU - Perdew, Gary H AU - Perdew GH LA - eng GR - R01 ES011834/ES/NIEHS NIH HHS/United States GR - ES11834/ES/NIEHS NIH HHS/United States GR - R01 ES004869/ES/NIEHS NIH HHS/United States GR - ES04869/ES/NIEHS NIH HHS/United States GR - R01 ES004869-20/ES/NIEHS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20071130 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (IGFBP1 protein, human) RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Aryl Hydrocarbon) RN - KG60484QX9 (Omeprazole) SB - IM MH - Base Sequence/drug effects/physiology MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Gene Expression Regulation/drug effects/physiology MH - Humans MH - Insulin-Like Growth Factor Binding Protein 1/*biosynthesis/genetics MH - Molecular Sequence Data MH - Omeprazole/*pharmacology MH - RNA, Messenger/biosynthesis/genetics MH - Receptors, Aryl Hydrocarbon/*biosynthesis/genetics PMC - PMC2527780 MID - NIHMS64070 EDAT- 2007/12/07 09:00 MHDA- 2008/03/25 09:00 PMCR- 2008/09/02 CRDT- 2007/12/07 09:00 PHST- 2007/12/07 09:00 [pubmed] PHST- 2008/03/25 09:00 [medline] PHST- 2007/12/07 09:00 [entrez] PHST- 2008/09/02 00:00 [pmc-release] AID - jpet.107.132241 [pii] AID - 10.1124/jpet.107.132241 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2008 Mar;324(3):1102-10. doi: 10.1124/jpet.107.132241. Epub 2007 Nov 30.