Nrf2-inducing anti-oxidation stress response in the rat liver--new beneficial effect of lansoprazole.
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.
2nd Department of Internal Medicine, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Yasunobu
Y
Yamashita
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Takashi
T
Ueyama
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Toshio
T
Nishi
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Yuta
Y
Yamamoto
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Akatsuki
A
Kawakoshi
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Shogo
S
Sunami
2nd Department of Internal Medicine, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Mikitaka
M
Iguchi
2nd Department of Internal Medicine, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Hideyuki
H
Tamai
2nd Department of Internal Medicine, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Kazuki
K
Ueda
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Takao
T
Ito
Department of Anatomy and Cell Biology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Yoshihiro
Y
Tsuruo
2nd Department of Internal Medicine, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
Masao
M
Ichinose
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D064747:Lansoprazole / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D013853:Thioacetamide; D064747:Lansoprazole