The inhibition by flavonoids of 2-amino-3-methylimidazo[4,5-f]quinoline metabolic activation to a mutagen: a structure-activity relationship study

Mutat Res. 1997 Sep 5;379(1):21-32. doi: 10.1016/s0027-5107(97)00085-7.


The mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Salmonella typhimurium TA98 is inhibited by flavonoids with distinct structure-antimutagenicity relationships (Edenharder, R., I. von Petersdorff I. and R. Rauscher (1993). Antimutagenic effects of flavonoids, chalcones and structurally related compounds on the activity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and other heterocyclic amine mutagens from cooked food, Mutation Res., 287, 261-274). With respect to the mechanism(s) of antimutagenicity, the following results were obtained here. (1) 7-Methoxy- and 7-ethoxyresorufin-O-dealkylase activities in rat liver microsomes, linked to cytochrome P-450-dependent 1A1 and 1A2 monooxygenases catalyzing oxidation of IQ to N-hydroxy-IQ (N-OH-IQ), were effectively inhibited by 16 flavonoids (IC50: 0.4-9.8 microM). Flavones and flavonols are in general more potent enzyme inhibitors than flavanones, isoflavones, and chalcones. Among flavones the presence of hydroxyl or methoxyl groups resulted in minor changes only. However, among flavonols and flavanones the parent compounds exerted the strongest inhibitory effects, which decreased in dependence on number and position 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 detected. (2) No effects of flavonoids on NADPH-dependent cytochrome P-450 reductase 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-polar compounds were inactive and a 50% inhibition was achieved only by some flavones and flavonols (IC50: 15.0-148 nmol/ml top agar). Within the flavone and flavonol subgroups inhibitory effects increased in dependence on number and position of hydroxyl functions. Isoflavones and flavanones, however, as well as glycosides, were inactive. Hydroxyl groups 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) generated comutagenic compounds. 4. Cytosolic activation of IQ to mutagenic metabolites as determined by experiments with the hepatic S105 fraction comprises about 10% of the mutagenicity after activation by the combined microsomal and cytosolic fractions (S9). The pattern of inhibition as produced by 20 flavonoids was closely similar to that observed with the S9 fraction. 5. In various experiments designed for modulation of the mutagenic response, it could be shown that further mechanisms of 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).

MeSH terms

  • Animals
  • Antimutagenic Agents / chemistry*
  • Antimutagenic Agents / pharmacology*
  • Biotransformation / drug effects
  • Cytochrome P-450 CYP1A1 / antagonists & inhibitors
  • Cytochrome P-450 CYP1A1 / pharmacokinetics
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 Enzyme System / pharmacokinetics
  • Flavonoids / chemistry*
  • Flavonoids / pharmacology*
  • Hydroxylation
  • Hydroxyquinolines / antagonists & inhibitors
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Mutagenicity Tests
  • Mutagens / pharmacokinetics*
  • Oxidoreductases / pharmacokinetics
  • Quinolines / antagonists & inhibitors*
  • Quinolines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Antimutagenic Agents
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Flavonoids
  • Hydroxyquinolines
  • Mutagens
  • Quinolines
  • 5-hydroxy-2-amino-3-methylimidazo(4,5-f)quinoline
  • 2-amino-3-methylimidazo(4,5-f)quinoline
  • Cytochrome P-450 Enzyme System
  • Oxidoreductases
  • methoxyresorufin-O-demethylase
  • Cytochrome P-450 CYP1A1