This study examined the effects of metabolic transformation of the common dietary flavonoid, quercetin, on its ability to protect low-density lipoprotein (LDL) from neutrophil-mediated modification. Quercetin was shown to be effective in protecting LDL against neutrophil-mediated modification at physiological concentrations (1 microM) and appears to act by inhibiting myeloperoxidase (MPO)-catalyzed oxidation (IC(50) = 1.0 microM). Quercetin was also shown to protect against radical-induced [2,2'-azobis(2-methylpropionamidine)dihydrochloride] oxidation (IC(50) = 1.5 microM). Studies of structure-activity relationships showed that methylation at the 3'-position or glucuronidation at the 3-position did not significantly affect inhibition by quercetin of the MPO activity, but conjugations at both positions significantly reduce its activity. Our results suggest that the common dietary flavonoid, quercetin, and some of its major in vivo metabolites are potential inhibitors of MPO at physiological concentrations. Dietary flavonoids that could modify MPO activity could protect lipoproteins from damage in chronic inflammatory states such as cardiovascular disease.