The metabolic stability of two potential cancer chemopreventive flavones, i.e. 5,7-dimethoxyflavone (5,7-DMF) and 3',4'-dimethoxyflavone (3',4'-DMF), compared with the non-methylated flavone galangin (3,5,7-trihydroxyflavone), was investigated in human hepatic preparations. Galangin, as expected, was extensively metabolized mainly by glucuronidation in human liver S9 fractions in the presence of appropriate co-factors. In contrast, 5,7-DMF and 3',4'-DMF were metabolically highly stable with only a small fraction of 3',4'-DMF undergoing oxidation. Consistent with the S9 fraction results, galangin was almost completely depleted after 2-h incubations in freshly plated hepatocytes. The hepatocytes also showed some metabolism of 3',4'-DMF, but virtually none of 5,7-DMF. In human liver microsomes, 5,7-DMF was more metabolically stable than 3',4'-DMF. The observations present a new strategy for examining the metabolic stability of dietary flavonoids and suggest that methylated flavonoids may have a high oral bioavailability compared with their non-methylated forms, which will make them more likely to be useful as cancer chemoprotectants.