title: 3-Hydro-2,2,5,6-tetramethylpyrazine: A novel inducer of zinc transporter-1 in HepG2 human hepatocellular carcinoma cells.
abstract: Dihydropyrazine compounds, including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are low-molecular-weight glycation products spontaneously generated in vivo and also ingested via food. Our preliminary study using microarray analysis demonstrated that DHP-3 induced zinc transporter-1 (ZnT-1) in HepG2 cells. It is well known that the increase of intracellular zinc is a sensitive stimulating factor for ZnT-1 protein induction; however, there is little information about the induction of ZnT-1 by low-molecular-weight chemical compounds. Here, we attempted to clarify the mechanism of ZnT-1 induction by DHP-3. A significant increase of ZnT-1 mRNA was observed 6h after DHP-3 treatment at concentrations over 0.5mM, and disappeared 24h after exposure. This induction pattern followed that of metal-responsive transcription factor 1 (MTF-1) mRNA, a metalloregulatory protein that serves as a major transcription factor of ZnT-1. Moreover, DHP-3 yielded transcriptional activation of MTF-1 in a luciferase reporter assay. The intracellular zinc content was unaffected by the compound; however, oxidative stress was observed in cells under the same conditions that activated the MTF-1 signaling pathway. These results suggest that DHP-3 is a novel ZnT-1 inducer and acts via activation of the MTF-1 signaling pathway. Additionally, the activation of MTF-1 by this compound likely occurs through oxidative stress.
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan. Electronic address: ishida@ph.sojo-u.ac.jp.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan. Electronic address: ta-yamaguchi@jcom.home.ne.jp.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan. Electronic address: stakechi@ph.sojo-u.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takechi
mesh_terms: D027682:Cation Transport Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D000097809:Transcription Factor MTF-1
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D008156:Luciferases; D011719:Pyrazines; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C000598211:3-hydro-2,2,5,6-tetramethylpyrazine; C498299:SLC30A1 protein, human
keywords: 3-Hydro-2,2,5,6-tetramethylpyrazine; Glycation product; Induction; Metal-responsive transcription factor 1; Oxidative stress; Zinc transporter-1