Genotoxicity Studies of Indole-3-carbinol and N-Methoxyindole-3-carbinol—The Effect of Sulphotransferases

Background: Glucosinolates, secondary metabolites present in Brassicales, and their breakdown products have demonstrated various biological effects, including anti-carcinogenic activities in some animal models. The active compounds include indole-3-carbinol (I3C) and N-methoxyindole-3-carbinol (NI3C). Building on these findings, several synthetic N-substituted I3Cs strongly inhibited the growth of human cancer cell lines. This effect was mediated by reactive intermediates formed by sulphotransferase (SULT) 1A1. Objective: We present genotoxicity findings on I3C and N-substituted derivatives, with special consideration given to SULTs. Methods: We review genotoxicity findings with I3C, NI3C and their parental glucosinolates. Then, we present some findings hitherto unpublished. Results: Neoglucobrassicin and its breakdown product NI3C demonstrated high genotoxic activity in vitro and formed high levels of DNA adducts in animal studies. These effects were strongly enhanced in the presence of SULT1A1. By contrast, glucobrassicin and I3C were weakly mutagenic. New observations include: enhanced activation of NI3C to a mutagen by human SULT1C4 compared to SULT1A1; SULT1A1-dependent genotoxicity of I3C (induction of sister chromatid exchange, SCE); cellular co-localisation of SULT1A1 and DNA adducts formed in the kidneys of NI3C-treated mice. Conclusions: I3C and NI3C are genotoxic in the presence of an appropriate SULT, but with large quantitative and qualitative differences (I3C required higher concentrations and induced only SCE, virtually no gene mutations). No information is available regarding the genotoxicity of other N-substituted I3C derivatives being developed as antineoplastic drugs. We suspect that they may greatly vary in this activity, which in turn might impact clinical effectiveness as well as adverse side-effects.