Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests

Abstract

3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the (32)P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts.

Identification of glucosinolate congeners able to form DNA adducts and to induce mutations upon activation by myrosinase

“…This reactivity has been studied primarily for isothiocyanates. They can undergo addition as well as substitution reactions with nucleophiles [1,3,26,27]. Substitution reactions have been observed primarily with benzylic isothiocyanates, a class that includes indolylmethyl isothiocyanates.…”

Scientific Opinion on Flavouring Group Evaluation 77, Revision 2 (FGE.77Rev2): Consideration of Pyridine, Pyrrole and Quinoline Derivatives evaluated by JECFA (63rd meeting) structurally related to Pyridine, Pyrrole, Indole and Quinoline Derivatives evalu

“…(Florin et al, 1980) Ames assay S. typhimurium TA98; TA100 Not reported Negative 3 (Kim et al, 1989) Ames assay (preincubation method) (Reddy et al, 2002) Aberrations were only detected at cytotoxic concentrations that (Florin et al, 1980) Single dose study.…”

Scientific Opinion on Flavouring Group Evaluation 77, Revision 1 (FGE.77Rev1): Consideration of Pyridine, Pyrrole and Quinoline Derivatives evaluated by JECFA (63rd meeting) structurally related to Pyridine, Pyrrole, Indole and Quinoline Derivatives evaluated by EFSA in FGE.24Rev2 (2013)

“…( (Ochiai et al, 1986) S. typhimurium TA100 Up to 3.33 mM (437 µg/ml) Negative 3 (Reddy et al, 2002) Mutation assay (paper-disk method)…”

“…Chinese hamster ovary cells 1.3, 1.4 and 1.5 mM (+ S9) 1.4, 1.5 and 1.6 mM (-S9) Positive 1 (Reddy et al, 2002) Aberrations were only detected at cytotoxic concentrations that showed marked inhibition of DNA (Florin et al, 1980) Single dose study.…”