Characterization of flavonoids as monofunctional or bifunctional inducers of quinone reductase in murine hepatoma cell lines.

The ability of flavonoid compounds to induce the activity of the phase II anticarcinogenic marker enzyme, quinone reductase (QR), has been studied in a wild-type murine hepatoma cell line (Hepalclc7) and in an Ah-receptor-defective mutant of the same cell line (Hepalclc7 bp(r)cl). The results showed that 10 (beta-naphthoflavone, kaempferide, tamarixetin, rhamnetin, quercetin, kaempferol, quercetin-4'-glucoside, isorhamnetin, daidzein and genistein) of the 13 flavonoids tested induced QR activity in the wild-type cells. Only the latter six also showed such activity in the bp(r)cl mutant, which indicates that they induce phase II enzymes directly (monofunctional inducers), whereas the others induce phase 11 enzymes only in cells with an operative Ah receptor system (bifunctional inducers). The metabolism of representatives of monofunctional (quercetin) and bifunctional (tamarixetin and rhamnetin) flavonol inducers were studied in both wild-type and bp(r)cl cells. In all cases, the major metabolites were glucuronides. Quercetin produced identical metabolites in both cell types, whereas one glucuronide of tamarixetin and two glucuronides of rhamnetin were not formed in the mutant cells. This shows that flavonoids can be mono- or bifunctional inducers depending on their chemical structure, and that the glucuronidation pattern of bifunctional inducers is altered by the presence of a functional Ah receptor system.