THE INHIBITION BY FLAVONOIDS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE METABOLIC-ACTIVATION TO A MUTAGEN - A STRUCTURE-ACTIVITY RELATIONSHIP STUDY

The mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Sa lmonella typhimurium TA98 is inhibited by flavonoids with distinct str ucture-antimutagenicity relationships (Edenharder, R., I. von Petersdo rff I. and R. Rauscher (1993) Antimutagenic effects of flavonoids, cha lcones and structurally related compounds on the activity of 2-amino-3 -methylimidazo[4,5-f]quinoline (IQ) and other heterocyclic amine mutag ens from cooked food, Mutation Res., 287, 261-274). With respect to th e mechanism(s) of antimutagenicity, the following results were obtaine d here. (1) 7-Methoxy- and 7-ethoxyresorufin-O-dealkylase activities i n rat liver microsomes, linked to cytochrome P-450-dependent 1A1 and 1 A2 monooxygenases catalyzing oxidation of IQ to N-hydroxy-IQ (N-OH-IQ) , were effectively inhibited by 16 flavonoids (IC50: 0.4-9.8 mu M). Fl avones and flavonols are in general more potent enzyme inhibitors than flavanones, isoflavones, and chalcones. Among flavones the presence o f hydroxyl or methoxyl groups resulted in minor changes only. However, among flavonols and flavanones the parent compounds exerted the stron gest inhibitory effects, which decreased in dependence on number and p osition of hydroxyl functions. Contrary to the results obtained in the Salmonella assay in the tests with alkoxyresorufins no extraordinary counteracting effects of isoflavones, of hydroxyl groups at carbons 6 or 2' or of the elimination of ring B (benzylideneacetone) were detect ed. (2) No effects of flavonoids on NADPH-dependent cytochrome P-450 r eductase activity could be detected. (3) The effects of 30 flavonoids on mutagenicity induced by N-OH-IQ in S. typhimurium TA98NR were again structure dependent. The most striking feature was the, in principle, reverse structure-antimutagenicity pattern as compared to IQ: non-pol ar compounds were inactive and a 50% inhibition was achieved only by s ome flavones and flavonols (IC50: 15.0-148 nmol/ml top agar). Within t he flavone and flavonol subgroups inhibitory effects increased in depe ndence on number and position of hydroxyl functions. Isoflavones and f lavanones, however, as well as glycosides, were inactive, Hydroxyl gro ups at carbons 7, 3', 4', and 5' generated antimutagenic compounds, a hydroxyl function at C5 was ineffective, but hydroxyls at C3 and 6 as well as methoxyl groups at C3' (isorhamnetin) or 4' (diosmetin) genera ted comutagenic compounds. 4. Cytosolic activation of IQ to mutagenic metabolites as determined by experiments with the hepatic S105 fractio n comprises about 10% of the mutagenicity after activation by the comb ined microsomal and cytosolic fractions (S9). The pattern of inhibitio n as produced by 20 flavonoids was closely similar to that observed wi th the S9 fraction. 5. In various experiments designed for modulation of the mutagenic response, it could be shown that further mechanisms o f flavonoid interaction with the overall mutagenic process may exist, such as interactions with biological membranes (luteolin, fisetin) and effects on fixation and expression of DNA damage (flavone, fisetin). (C) 1997 Elsevier Science B.V.