title: Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2-related factor 2.
abstract: Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM-mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms.
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ananddeep
authors.initials: A
authors.lastname: Patel
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: shivanna@bcm.edu.
authors.forename: Binoy
authors.initials: B
authors.lastname: Shivanna
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005333:Fetus; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology*; D061251:Primary Cell Culture; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D009853:Omeprazole
keywords: Aryl hydrocarbon receptor; Cytochrome P450 1A1; Fetal human pulmonary microvascular endothelial cells; NAD(P)H quinone oxidoreductase 1; Nuclear factor erythroid 2–related factor 2; Omeprazole