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

Breakdown products of some glucosinolates defense chemicals of Brassicales induce detoxifying enzymes and demonstrate preventive activities against chemically induced tumorigenesis 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 was enhanced in mice transgenic for human sulphotransferases 1A1/2 (FVB/N-hSULT1A1/2). In this study we explored gene expression changes induced by 1-MIM-OH in mouse liver. 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 analyzes in this tissue 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. In conclusion, 1-MIM-OH did not induce protective enzymes, but formed high levels of DNA adducts, which were recognized by affected cells as reflected by p53 activation. While this p53 response might aim to protection, it was unable to prevent the accumulation of DNA adducts. However, various epdemiological studies reported inverse associations between the intake of cruciferous vegetables and cancer. This association might be due to the presence of other glucosinolates with tumour-preventing influences possibly outweighing adverse effects of some metabolites. Nevertheless, 1-MIM-OH is a genotoxic substance inducing a gene expression profile similar to the expression signature caused by known genotoxic hepatocarcinogens.

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Ehlers A, Florian S, Schumacher F, Meinl W, Lenze D, Hummel M, Heise T, Seidel A, Glatt H, Lampen A