title: The glucosinolate metabolite 1-methoxy-3-indolylmethyl alcohol induces a gene expression profile in mouse liver similar to the expression signature caused by known genotoxic hepatocarcinogens.
abstract: METHODS
  Breakdown products of certain glucosinolates induce detoxifying enzymes and demonstrate preventive activities against chemically induced tumourigenesis in animal models. However, other breakdown products are genotoxic. 1-Methoxy-3-indolylmethyl alcohol (1-MIM-OH) is mutagenic in bacterial and mammalian cells upon activation by sulphotransferases and forms DNA adducts in mouse tissues. This effect is enhanced in mice transgenic for human sulphotransferases 1A1/2 (FVB/N-hSULT1A1/2). Therefore, we explored gene expression changes induced by 1-MIM-OH in mouse liver.
  
  
  RESULTS
  FVB/N-hSULT1A1/2 mice were orally treated with 1-MIM-OH for 21 or 90 days, leading to high levels of hepatic 1-MIM-DNA adducts. Genome-wide expression analyses demonstrated no influence on detoxifying enzymes, but up-regulation of many mediators of the tumour suppressor p53 and down-regulation of Fhit and other long genes. While this p53 response might indicate protection, it was unable to prevent the accumulation of DNA adducts. However, various epidemiological studies reported inverse associations between the intake of cruciferous vegetables and cancer. This association may be due to the presence of other glucosinolates with tumour-preventing influences possibly outweighing adverse effects of some metabolites.
  
  
  CONCLUSIONS
  1-MIM-OH is a genotoxic substance inducing a gene expression profile similar to the expression signature caused by known genotoxic hepatocarcinogens.
authors.affiliation: Department of Food Safety, Federal Institute for Risk Assessment (BfR), Berlin, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Ehlers
authors.forename: Simone
authors.initials: S
authors.lastname: Florian
authors.forename: Fabian
authors.initials: F
authors.lastname: Schumacher
authors.forename: Walter
authors.initials: W
authors.lastname: Meinl
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Tanja
authors.initials: T
authors.lastname: Heise
authors.forename: Albrecht
authors.initials: A
authors.lastname: Seidel
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018736:DNA Adducts / Q000378:metabolism; D015536:Down-Regulation; D005961:Glucosinolates / Q000737:chemistry*; D008658:Inactivation, Metabolic; D007211:Indoles / Q000737:chemistry*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D018736:DNA Adducts; D005961:Glucosinolates; D007211:Indoles; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D000099170:Bis(5'-adenosyl)triphosphatase; C410766:N-methoxyindole-3-carbinol
keywords: DNA adducts; Fhit; Gene expression profiles; Genotoxic hepatocarcinogens; Glucosinolates; p53