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 theri derivatives including flavones, flavonols, flavanoes, inoflavones and flavanols were determined using Salmonella typhimurium TA98 against 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) in the presence of Aroclor 1254-induced rat hepatic S9. In general, a relationship between the chemical structure of flavonoids and their antimutagenicity was found for compounds containing one or more of the following featutes: (i) C4 keto group, (ii) aglycone, (iii double bond at positions C2 and C3, (iv) phenyl group at position C2, and (v) three hydroxyl substituents at positons C4', C5 and C7. The inhibitory effects of flavonoids on activities of 7-ethoxycoumarin deethylase (ECD) and 7-ethoxyresorufin deethylase (ESD) of Aroclor 12540-induced hepatic microsomes were also examined. In addition, we studied the effects of flavonoids on the metabolism of IQ by Aroclor 1254-induced microsomes using high-performance liquid chromatography. The antimutagenicity correlated with the inhibition of cytochrome P-450IA1-linked ESD and P-450IA2-linked ECD activity in hepatic microsomes, and with an inhibition of N-hydroxy-IQ fromation from IQ metabolism by hepatic microsomes. These reslute indicated that flavones or flavonols that contasin C5, C7 and C4' hydroxyl groups are potent inhibitors of P-450 enzyme activities induced by Aroclor 1254 (P-450IA1 and P-450IA2), and masy potentially be useful as chemopreventive agents against heterocyclic amine-induced mutagenesis or carcinogenesis.