THE STRUCTURE-ACTIVITY-RELATIONSHIPS OF FLAVONOIDS AS INHIBITORS OF CYTOCHROME-P-450 ENZYMES IN RAT-LIVER MICROSOMES AND THE MUTAGENICITY OF 2-AMINO-3-METHYL-IMIDAZO[4,5-F]QUINOLINE

The antimutagenicity of 19 naturally occurring flavonoids and their de rivatives including flavones, flavonols, flavanones, isoflavones and f lavanols were determined using Salmonella typhimurium TA98 against 2-a mino-3-methylimidazo[4,5-f] quinoline (IQ) in the presence of Aroclor 1254-induced rat hepatic S9. In general, a relationship between the ch emical structure of flavonoids and their antimutagenicity was found fo r compounds containing one or more of the following features: (i) C4 k eto group, (ii) aglycone, (iii) double bond at positions C2 and C3, (i v) phenyl group at position C2, and (v) three hydroxyl substituents at positions C4', C5 and C7. The inhibitory effects of flavonoids on act ivities of 7-ethoxy-coumarin deethylase (ECD) and 7-ethoxyresorufin de ethylase (ESD) of Aroclor 1254-induced hepatic microsomes were also ex amined. In addition, we studied the effects of flavonoids on the metab olism of IQ by Aroclor 1254-induced microsomes using high-performance liquid chromatography. The antimutagenicity correlated with the inhibi tion of cytochrome P-450IA1-linked ESD and P-450IA2-linked ECD activit y in hepatic microsomes, and with an inhibition of N-hydroxy-IQ format ion from IQ metabolism by hepatic microsomes. These results indicated that flavones or flavonols that contain C5, C7 and C4' hydroxyl groups are potent inhibitors of P-450 enzyme activities induced by Aroclor 1 254 (P-450IA1 and P-450IA2), and may potentially be useful as chemopre ventive agents against heterocyclic amine-induced mutagenesis or carci nogenesis.