ANTIMUTAGENICITY OF FLAVONES AND FLAVONOLS TO HETEROCYCLIC AMINES BY SPECIFIC AND STRONG INHIBITION OF THE CYTOCHROME-P450 1A FAMILY

We found the mechanism in flavonoids that can strongly suppress the mu tagenicity of one of the food-derived and carcinogenic heterocyclic am ines, 3-amino-1-methyl-5-H-pyrido[4,3-b]indole (Trp-P-2). The antimuta genicity was evaluated by IC50 value, the amount required for 50 % inh ibition of the mutagenicity of 0.1 nmol Trp-P-2, with Salmonella typhi murium TA98 strain in the presence of S9 mix. The flavones and flavono ls were two orders stronger as antimutagens than such antimutagenic ph ytochemicals as chlorophylls and catechins. We had previously found fl avonoids to be a desmutagen to neutralize Trp-P-2 before or during att ack of DNA, because they had no effect on either the ultimate mutageni c form of Trp-P-2 (N-hydroxy-Trp-P-2) or the mutated cells. The desmut agenicity of the flavonoids did not depend on the hydroxy number or po sition that should be associated with antioxidative potency, and was a lso unaffected by the solubility of Trp-P-2 in the assay solution. The inhibitory effect of the flavonoids on the metabolic activation of Tr p-P-2 to N-hydroxy-Trp-P-2 was almost in parallel with the antimutagen ic IC50 value, when determined with a Saccharomyces cerevisiae AH22 ce ll simultaneously expressing both rat cytochrome P450 1A1 and yeast re ductase. The K-i values of flavones and flavonols for the enzyme were less than 1 mu M, while the K-m value of Trp-P-2 was 25 mu M. The anti mutagenicity of the flavones and flavonols was thus concluded to be du e to inhibition of the activation process of Trp-P-2 by P450 1A1 to th e ultimate carcinogenic form. They were also able to act as antimutage ns toward other indirect mutagens that were activated by P450 1A1.