Flavonoids exhibit prooxidant cytotoxicity in mammalian cells due to the formation of
free radicals and oxidation products possessing
quinone or quinomethide structure. However, it is unclear how the cytotoxicity of
flavonoids depends on the ease of their single-electron oxidation in aqueous medium, i.e., the redox potential of the
phenoxyl radical/
phenol couple. We verified the previously calculated redox potentials for several
flavonoids according to their rates of reduction of
cytochrome c and
ferricyanide, and proposed experimentally-based values of redox potentials for
myricetin,
fisetin,
morin,
kaempferol,
galangin, and
naringenin. We found that the cytotoxicity of
flavonoids (n=10) in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) and murine
hepatoma (line MH-22a) increases with a decrease in their redox potential of the
phenoxyl radical/
phenol couple and an increase in their lipophilicity. Their cytotoxicity was decreased by
antioxidants and inhibitors of
cytochromes P-450, α-naphthoflavone and isoniazide, and increased by an inhibitor of
catechol-O-methyltransferase,
3,5-dinitrocatechol. It shows that although the prooxidant action of
flavonoids may be the main factor in their cytotoxicity, the hydroxylation and oxidative demethylation by
cytochromes P-450 and O-methylation by
catechol-O-methyltransferase can significantly modulate the cytotoxicity of the parent compounds.