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Formation of DNA Adducts by 1-Methoxy-3-indolylmethylalcohol, a Breakdown Product of a Glucosinolate, in the Mouse: Impact of the SULT1A1 Status-Wild-Type, Knockout or Humanised.
Glatt, Hansruedi; Weißenberg, Sarah Yasmin; Ehlers, Anke; Lampen, Alfonso; Seidel, Albrecht; Schumacher, Fabian; Engst, Wolfram; Meinl, Walter.
Afiliação
  • Glatt H; Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
  • Weißenberg SY; Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
  • Ehlers A; Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
  • Lampen A; Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
  • Seidel A; Department Food Safety, Federal Institute of Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
  • Schumacher F; Biochemical Institute for Environmental Carcinogens (BIU), Prof. Dr. Gernot Grimmer-Foundation, Lurup 4, 22927 Grosshansdorf, Germany.
  • Engst W; Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
  • Meinl W; Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2-4, 14195 Berlin, Germany.
Int J Mol Sci ; 25(7)2024 Mar 29.
Article em En | MEDLINE | ID: mdl-38612635
ABSTRACT
We previously found that feeding rats with broccoli or cauliflower leads to the formation of characteristic DNA adducts in the liver, intestine and various other tissues. We identified the critical substances in the plants as 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate and its degradation product 1-MIM-OH. DNA adduct formation and the mutagenicity of 1-MIM-OH in cell models were drastically enhanced when human sulfotransferase (SULT) 1A1 was expressed. The aim of this study was to clarify the role of SULT1A1 in DNA adduct formation by 1-MIM-OH in mouse tissues in vivo. Furthermore, we compared the endogenous mouse Sult1a1 and transgenic human SULT1A1 in the activation of 1-MIM-OH using genetically modified mouse strains. We orally treated male wild-type (wt) and Sult1a1-knockout (ko) mice, as well as corresponding lines carrying the human SULT1A1-SULT1A2 gene cluster (tg and ko-tg), with 1-MIM-OH. N2-(1-MIM)-dG and N6-(1-MIM)-dA adducts in DNA were analysed using isotope-dilution UPLC-MS/MS. In the liver, caecum and colon adducts were abundant in mice expressing mouse and/or human SULT1A1, but were drastically reduced in ko mice (1.2-10.6% of wt). In the kidney and small intestine, adduct levels were high in mice carrying human SULT1A1-SULT1A2 genes, but low in wt and ko mice (1.8-6.3% of tg-ko). In bone marrow, adduct levels were very low, independently of the SULT1A1 status. In the stomach, they were high in all four lines. Thus, adduct formation was primarily controlled by SULT1A1 in five out of seven tissues studied, with a strong impact of differences in the tissue distribution of mouse and human SULT1A1. The behaviour of 1-MIM-OH in these models (levels and tissue distribution of DNA adducts; impact of SULTs) was similar to that of methyleugenol, classified as "probably carcinogenic to humans". Thus, there is a need to test 1-MIM-OH for carcinogenicity in animal models and to study its adduct formation in humans consuming brassicaceous foodstuff.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adutos de DNA / Glucosinolatos Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adutos de DNA / Glucosinolatos Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article