Abstract

Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10–100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase II drug-metabolizing systems, i.e. the AhR/Cyp1a1/Nrf2 pathway in hepatocytes.

Highlights

  • Lansoprazole is a potent proton pump inhibitor that reduces the secretion of gastric acid from gastric parietal cells by inhibition of H+/K+-adenosine triphosphatase

  • We report for the first time that lansoprazole up-regulates the aryl hydrocarbon receptor (AhR)/Cyp1a1/Nrf2 pathway in hepatocytes and has a potential application in the prevention and treatment of oxidative hepatic damage

  • The levels of Nrf2 mRNA were increased at 3 h in a dosedependent manner, with a 2-fold increase observed at 100 mg/kg, as compared to control levels (Figure 1A)

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Summary

Introduction

Lansoprazole is a potent proton pump inhibitor that reduces the secretion of gastric acid from gastric parietal cells by inhibition of H+/K+-adenosine triphosphatase. Recent studies have shown that lansoprazole has acid-independent protective effects in the gastrointestinal mucosa, such as anti-inflammatory effects and anti-bacterial effects on Helicobactor pylori [3]. Induction of the antioxidant defense enzyme, heme oxygenase-1 (HO-1) in human endothelial and gastric cancer cells, rat gastric epithelial cells (RGM-1), or the epithelium of small intestine is involved in acid-independent gastrointestinal mucosal protection [5,6,7]. These reports demonstrated that lansoprazole, but not omeprazole, induced HO-1 in gastric mucosal cells [6] and the small intestine [7]. We used lansoprazole to investigate anti-oxidative stress responses in the liver

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