title: Breakdown products of neoglucobrassicin inhibit activation of Nrf2 target genes mediated by myrosinase-derived glucoraphanin hydrolysis products.
abstract: Glucosinolates (GLSs) present in Brassica vegetables serve as precursors for biologically active metabolites, which are released by myrosinase and induce phase 2 enzymes via the activation of Nrf2. Thus, GLSs are generally considered beneficial. The pattern of GLSs in plants is various, and contents of individual GLSs change with growth phase and culture conditions. Whereas some GLSs, for example, glucoraphanin (GRA), the precursor of sulforaphane (SFN), are intensively studied, functions of others such as the indole GLS neoglucobrassicin (nGBS) are rather unknown as are functions of combinations thereof. We therefore investigated myrosinase-treated GRA, nGBS and synthetic SFN for their ability to induce NAD(P)H:quinone oxidoreductase 1 (NQO1) as typical phase 2 enzyme, and glutathione peroxidase 2 (GPx2) as novel Nrf2 target in HepG2 cells. Breakdown products of nGBS potently inhibit both GRA-mediated stimulation of NQO1 enzyme and Gpx2 promoter activity. Inhibition of promoter activity depends on the presence of an intact xenobiotic responsive element (XRE) and is also observed with benzo[a]pyrene, a typical ligand of the aryl hydrocarbon receptor (AhR), suggesting that suppressive effects of nGBS are mediated via AhR/XRE pathway. Thus, the AhR/XRE pathway can negatively interfere with the Nrf2/ARE pathway which has consequences for dietary recommendations and, therefore, needs further investigation.
authors.affiliation: German Institute of Human Nutrition Potsdam-Rehbrücke, Department Biochemistry of Micronutrients, Nuthetal, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Haack
authors.forename: Maria
authors.initials: M
authors.lastname: Löwinger
authors.forename: Doris
authors.initials: D
authors.lastname: Lippmann
authors.forename: Anna
authors.initials: A
authors.lastname: Kipp
authors.forename: Eleonora
authors.initials: E
authors.lastname: Pagnotta
authors.forename: Renato
authors.initials: R
authors.lastname: Iori
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Monien
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.forename: Martin N
authors.initials: MN
authors.lastname: Brauer
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohé
mesh_terms: D001564:Benzo(a)pyrene; D001937:Brassica / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D005961:Glucosinolates / Q000378:metabolism* / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D006868:Hydrolysis; D007096:Imidoesters / Q000378:metabolism* / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology*; D017879:Isothiocyanates; D016297:Mutagenesis, Site-Directed; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010091:Oximes; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000138:chemical synthesis / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D005961:Glucosinolates; D007096:Imidoesters; D007211:Indoles; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010091:Oximes; D018336:Receptors, Aryl Hydrocarbon; D013454:Sulfoxides; D013861:Thiocyanates; D015262:Xenobiotics; C555404:neoglucobrassicin; D001564:Benzo(a)pyrene; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D006026:Glycoside Hydrolases; C022739:thioglucosidase; C016766:sulforaphane; C119494:glucoraphanin