Catechol estrogens have been postulated to mediate estradiol-induced kidney tumorigenesis in Syrian hamsters. As part of an examination of this postulate, we studied the influence of quercetin, a polyphenolic flavonoid, on the incidence and severity of estrogen-induced kidney tumors, on the metabolic activation of estradiol to catechol estrogens, and on the inactivation of catechol estrogens by catechol-O-methyltransferase-mediated O-methylation. None of the hamsters treated with 0.3 or 3% quercetin in the diet for 5.7 or 6.5 months, respectively, developed tumors, whereas all animals treated with estradiol developed kidney tumors. The coadministration of estradiol plus 3% quercetin significantly (p < 0.05) increased the mean number of large tumor nodules and the incidence of abdominal metastases over values obtained with hormone treatment alone. The coadministration of estradiol plus 0.3 or 3% quercetin for 16 days increased renal NADPH-dependent estradiol-4- but not estradiol-2-hydroxylase activities by 91 or 73%, respectively, over values obtained with hormone treatment alone. In vitro, quercetin and its structural analog, fisetin, strongly inhibited the catechol-O-methyltransferase-catalyzed O-methylation of 60 microM 4-hydroxyestradiol, with IC50 values of approximately 2-4 microM. Kinetic analyses of the enzyme inhibition by quercetin and fisetin revealed a mixed-type of inhibition (competitive plus non-competitive). Combined treatment of estradiol plus 3% quercetin decreased the rates of kidney catechol-O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by 34 and 22%, respectively, from values obtained with hormone treatment alone. Rates of hamster liver and kidney microsome-mediated estrogen quinone formation and quinone reduction (redox cycling) in estradiol plus 3% quercetin-treated hamsters were not markedly altered compared to values obtained in estradiol-treated animals. It is concluded that increased rates of formation of 4-hydroxyestradiol combined with an inhibition of the inactivation of this catechol estrogen by catechol-O-methyltransferase may result in elevated levels of this estrogen metabolite, specifically in the hamster kidney, where it may undergo metabolic redox cycling and generate potentially mutagenic free radicals. Thus, the potentiation by quercetin of estradiol-induced tumorigenesis in hamster kidney supports a role of 4-hydroxyestradiol in estrogen-induced carcinogenesis in this species.