Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids.

Myricetin, robinetin and luteolin inhibited the mutagenic activity resulting from the metabolic activation of benzo[a]-pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene by rat liver microsomes. These naturally occurring plant flavonoids and seventeen additional flavonoids and related derivatives with phenolic hydroxyl groups inhibited the mutagenic activity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), which is an ultimate mutagenic and carcinogenic metabolite of benzo[a]pyrene. Several flavonoids without phenolic hydroxyl groups or with methylated phenolic hydroxyl groups were inactive. The mutagenic activity of 0.05 nmol of BP 7,8-diol-9,10-epoxide-2 towards strain TA 100 of S. typhimurium was inhibited 50% by incubation of the bacteria and the diol-epoxide with myricetin (2 nmol), robinetin (2.5 nmol), luteolin (5 nmol), quercetin (5 nmol), 7-methoxyquercetin (5 nmol), rutin (5 nmol), quercetin (5 nmol), delphinidin chloride (5 nmol), morin (10 nmol), myricitrin (10 nmol), kaempferol (10 nmol), diosmetin (10 nmol), fisetin (10 nmol), or apigenin (10 nmol). Considerably less antimutagenic activity was observed for dihydroquercetin, naringenin, robinin, D-catechin, genistein, kaempferide and chrysin. Pentamethoxyquercetin, tangeretin, nobiletin, 7,8-benzoflavone, 5,6-benzoflavone, and flavone, which lack free phenolic groups, were inactive. The antimutagenic activity of hydroxylated flavonoids results from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2 since the rate of disappearance of the diol-epoxide from cell-free solutions in 1:9 dioxane:water was markedly stimulated by myricetin, robinetin and quercetin. Myricetin was a highly potent inhibitor of the mutagenic activity of bay-region diol-epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene and dibenzo[a,i]pyrene, but higher concentrations of myricetin were needed to inhibit the mutagenicity of the chemically less reactive benzo[a]pyrene 4,5-oxide and bay region diol-epoxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene.