Flavonols, mutagenic

The structural requirements for 8-hydroxyflavone activation are distinct from those for flavonols such as quercetin or kaempferol. Whereas B-ring hydroxylation, 2,3-unsaturation, and 3-hy-droxylation appear critical for flavonol mutagenicity, the B-ring and 2,3-positions do not appear to be involved in the activation of 8-substituted flavones. The 5,7,8-substitution pattern on the A-ring is particularly effective at conferring high activity in the flavone series. The seven most active compounds known at present all have -OH or -OCH substituents at these positions. 

It is important to determine if the observed in vitro genotoxic effects are due to direct interaction of flavonoid-derived intermediates with DNA, or whether the genotoxicity is secondary to the interaction of the flavonoid with biochemical processes which affect the fidelity of DNA replication. The structural and metabolic requirements for flavonol mutagenicity are consistent with a requirement for generation of DNA-reactive quininoid intermediates (see above), but no direct evidence for direct DNA modification by flavonoids has yet been obtained. In mammalian cells, such structure-activity studies are not yet available. 

FlESCHi M, CODIGNOLA A and Luppi MOSCA A M (1989) Mutagenic flavonol aglycones in infusions and in fresh and pickled vegetables , JFood Sci, 42, 1492-5. 

Procyanidins with different degrees of polymerization such as dimers, trimers, and polymers from extracts of different natural sources were found to be nonmutagenic in the Salmonella mutagenesis assay. Moreover, the mutagenic impurity in procyanidin B-4 was isolated by reversed-phase high-performance liquid chromatography (HPLC). Procyanidin B-4 was identified as rutin (flavonol O-glycoside, 3) (Fig. 22) [55]. 

Starting In 1977, papers dealing with this topic have come from half a dozen different laboratories (13-18). The amount of data Is considerable and, where the results of various Investigators overlap, there Is fairly substantial agreement. The kinds of flavonoids that have been studied. In free or combined form, are the flavones, Isoflavones, flavonols, flavanones, dlhydro-chalcones, catechlns and anthocyanlns. Of these, only the flavonols show any appreciable mutagenicity but It must be emphasized that not all flavonols are mutagenic. 

Flavonols 6-18 are not mutagenic by themselves but become so when exposed to S-9 or. In the case of glycosides, to a glycoside-hydrolyzing enzyme. (Myricitrin (28) would doubtlessly become active in the presence of a hydrolytic enzyme.) The remaining flavonols (19-28), as well as the known or postulated metabolites of quercetin (29-33), are inactive even if treated with S-9. 

Quercetin (2) is easily the most active flavonol in the Salmonella test, yet it is at least an order of magnitude less potent than such familiar mutagens as benz[a]pyrene and chrysene. Quercetin, galangin (6), kaempferol (7) and rhamnetln (3) are more or less active in several other in vitro tests designed to detect genetic toxicity. For example, quercetin has been shown to transform hamster embryo cells (kaempferol did not)... 

Table I. The Mutagenicity of Some Naturally Occurring Flavonols and Related Substances in the... 

In the Ames test for mutagenicity, ethanol extracts of arnica produced a two- to fourfold increase in the number of rever-tants, as compared to controls with S. typhimurium TA98 with and without metabolic activation and with S. typhimurium TAIOO with metabolic activation an increase was not seen with TAIOO without metabolic activation (Goggelmann and Schimmer 1986). The authors indicated that the effect was likely due to the flavonol compounds in arnica, noting that "the origin of the plant is important for the presence of essential components" and that results can differ based on the district of growth and the preparation of the extract (Goggelmann and Schimmer 1986). 

In the Ames test for mutagenicity, weak mutagenic activity was observed, a frequent response from plant materials containing flavonols (Goggleman and Schimmer 1986). 

Brown, J.P., and P.S. Dietrich. 1979. Mutagenicity of plant flavo-nols in the Salmonella/maminalian microsome test Activation of flavonol glycosides by mixed glycosidases from rat cecal bacteria and other sources. Mutat. Res. 66(3) 223-240. 

Brown, J.P., P.S. Dietrich, and R.J. Brown. 1977. Frameshift mutagenicity of certain naturally occurring phenolic compoimds in the Salmonella/microsome test Activation of anthraquinone and flavonol glycosides by gut bacterial enzymes. Biochem. Soc. Trans. 5(5) 1489-1492. 

In summary, there are at least two distinct classes of flavo-noids mutagenic in Salmonella tvphimurium. The first class is most active in strains TA98 and TA97, with lesser, but still marked, activity in strain TAIOO. To date, only flavonols have exhibited this type of activity. Activation of these flavonols may involve oxidation of hydroxyl groups in ring-B to quininoid intermediates. The presence of a free hydroxyl at position-3 and a double bond at the 2,3-position are critical for activity. 

Hardigree, A.A. and Epier, J.L. (1977). Mutagenicity of plant flavonols In microbial systems. Abstr. 8th Ann. Mto. Environmental Mutaoen Society. Colorado Springs, Colorado, p. 48. 

Brown J P, Dietrich P S 1979 Mutagenicity of plant flavonols in the salmonella mammalian microsome test. Activation of flavonol glycoside by mixed glycosidases from rat fecal bacteria and other sources. Mutat Res 66 223-240... 

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