Genetic toxicology of flavonoids: the role of metabolic conditions in the induction of reverse mutation, SOS functions and sisterchromatid exchanges

Abstract

Glycosides of flavonols such as quercetin, are found in the edible portions of most food vegetables. Flavonols present in plants as glycosides can be freed during fermentation. We have compared the DNA-damaging activity of quercetin, rutin (3-o-rutinoside of quercetin) and a fermented flavonoid-containing beverage, red wine, for different genetic end-points under different metabolic conditions. The genotoxicity of quercetin, rutin and commercial red wine has been studied for the induction of: (i) reverse mutation in the Ames assay; (ii) SOS functions in the SOS Chromotest; (iii) sister-chromatid exchanges (SCEs) in human lymphocytes. While in the Ames assay the mutagenicity of quercetin is enhanced by the presence of rat liver microsomal enzymes (S9) or the respective cytosolic fraction (S100), genotoxicity is reduced when the induction of SOS responses is assessed using the SOS Chromotest. Similarly, the induction of SCEs is lowered when testing in the presence of liver enzymes. Rutin has no activity whatsoever. Detection of activity of red wine in the three assays is not dependent upon hydrolysis by glycosidases and its content of quercetin accounts almost entirely for the levels of genotoxicity detected. The results suggest that the putative genotoxic metabolites of quercetin vary for different genetic end-points considered and that the metabolic fate of flavonoids might partly account for the conflicting data about their genotoxicity in vivo and carcinogenic activity.

Possible Synergistic Effect and Antioxidant Properties of Chitosan Nanoparticles and Quercetin against Carbon Tetrachloride-Induce Hepatotoxicity in Rats

“…Moreover, In Escherichia coli, quercetin has been shown to induce SOS activity, reverse mutations, and DNA single strand breaks with or without metabolic activation [46]- [49]. These positive mutagenic and genotoxic responses in bacterial test systems have been confirmed in eukaryotic cells, including yeast [50] and mammalian cells included mouse, hamster, rat and human [51]- [55], in which sister chromatid exchanges, chromosomal aberrations, unscheduled DNA synthesis (UDS), and micronucleus formation are among some of the endpoints evaluated. However, in a study for a 2-year rodent carcinogenicity bioassay conducted by the National Toxicology Program (NTP), these genotoxic effects have not confirmed suggesting the safety of quercetin for oral consumption in humans [52] [56] [57].…”

Dose-related effects of Quercetin in the human breast carcinoma MCF-7 cell line

“…The induction of SOS activity, reverse mutation and DNA single strand breaks in the presence or absence of metabolic activation has been observed in Escherichia coli (Hardigree & Epler, 1978;Llagostera et al, 1987;Rueff et al, 1986). Similarly, mutagenic and genotoxic activities of quercetin has been confirmed in eukaryotic cells (Hardigree & Epler, 1978) and mammalian cells (Yoshida et al, 1980;Van der Hoeven et al, 1984;Rueff et al, 1986;Kubiak & Rudek, 1990;Gasper et al, 1994;Caria et al, 1995). In these various studies, sister chromatid exchange, chromosomal aberrations, unscheduled DNA synthesis (UDS) and micronucleus formation were endpoints evaluated.…”

“…Several studies confirmed and extended the initial observations of Bjeldanes and Chang (1977) and thus established quercetin as one of the most mutagenic flavonoids. (MacGregor & Jurd, 1978;Brown & Dietrich, 1979;Rueff et al, 1986). In vivo evaluation of quercetin showed its ability to act as a genotoxicant causing damage at the post meiotic stage of spermatogenesis in experimental rats.…”

“…Irrespective of metabolic activation, quercetin has displayed positive mutagenic activity when tested in vitro in most standard strains of Salmonella typhimirium (Bjeldanes & Chang, 1977;Hardigree & Epler, 1978;Brown & Dietrich, 1979;Ochiai et al, 1984;Hatcher & Bryan, 1985;Schimmer et al, 1988;Vrijsen et al, 1990). The induction of SOS activity, reverse mutation and DNA single strand breaks in the presence or absence of metabolic activation has been observed in Escherichia coli (Hardigree & Epler, 1978;Llagostera et al, 1987;Rueff et al, 1986). Similarly, mutagenic and genotoxic activities of quercetin has been confirmed in eukaryotic cells (Hardigree & Epler, 1978) and mammalian cells (Yoshida et al, 1980;Van der Hoeven et al, 1984;Rueff et al, 1986;Kubiak & Rudek, 1990;Gasper et al, 1994;Caria et al, 1995).…”

“…The genotoxicity of quercetin is documented to be enhanced by cytosolic enzymes (Brown & Dietrich, 1979) as a protective effect of degradation afforded by superoxide-dismutase (SOD) present in S9 (Ochiai et al, 1984). Early studies noted based on cultured mammalian cells in test systems that the genotoxicity of quercetin is not increased in the presence of metabolic activation by S9 (van der Hoeven et al, 1984;Rueff et al, 1986). Quercetin has been documented to induce micronuclei in human lymphocytes in the absence of metabolic activation (Popp & Shimmer, 1991).…”