Nrf2-inducing anti-oxidation stress response in the rat liver--new beneficial effect of lansoprazole

• Published in: PloS one 2014-05, Vol.9 (5), p.e97419
• Main Authors: Yamashita, Yasunobu, Ueyama, Takashi, Nishi, Toshio, Yamamoto, Yuta, Kawakoshi, Akatsuki, Sunami, Shogo, Iguchi, Mikitaka, Tamai, Hideyuki, Ueda, Kazuki, Ito, Takao, Tsuruo, Yoshihiro, Ichinose, Masao
• Format: Article
• Language: English
• Subjects: Acids; Active Transport, Cell Nucleus - drug effects; Adenosine triphosphatase; Animals; Antioxidants; Antioxidants - metabolism; Aromatic compounds; Biology; Biology and Life Sciences; Cancer; Cell Nucleus - metabolism; Cytochrome; Cytochrome P-450; Cytochrome P450; Cytoplasm; Damage prevention; Data mining; Data processing; DNA microarrays; Dose-Response Relationship, Drug; Enzymes; Gastrointestinal agents; Gene expression; Genomics; Glucuronosyltransferase; Glutathione; Glutathione transferase; Heme; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Hydrocarbons; Immunohistochemistry; Internal medicine; Lansoprazole; Lansoprazole - pharmacology; Liver; Liver - metabolism; Liver - pathology; Lysates; Male; Medicine; Medicine and Health Sciences; Metabolism; NAD; NF-E2-Related Factor 2 - metabolism; Nuclear transport; Nuclei (nuclear physics); Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxygenase; Polypeptides; Pretreatment; Proteins; Quinone; Quinones; Rats; Rats, Wistar; Regulations; RNA; Rodents; Thioacetamide; Thioacetamide - toxicity; Transcription factors; Translocation; Ulcers; University graduates; Up-Regulation - drug effects; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0097419

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.