Flavonoids as Substrates and Inhibitors of Myeloperoxidase: Molecular Actions of Aglycone and Metabolites

• Published in: Chemical research in toxicology 2008-08, Vol.21 (8), p.1600-1609
• Main Authors: Shiba, Yuko, Kinoshita, Takashi, Chuman, Hiroshi, Taketani, Yutaka, Takeda, Eiji, Kato, Yoji, Naito, Michitaka, Kawabata, Kyuichi, Ishisaka, Akari, Terao, Junji, Kawai, Yoshichika
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antioxidants - chemistry; Antioxidants - pharmacology; Aorta - chemistry; Aorta - metabolism; Aorta - pathology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Computer Simulation; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Free Radical Scavengers - metabolism; HL-60 Cells; Humans; Macrophages - drug effects; Macrophages - enzymology; Peroxidase - antagonists & inhibitors; Peroxidase - metabolism; Quantitative Structure-Activity Relationship; Quercetin - analogs & derivatives; Quercetin - chemistry; Quercetin - pharmacology; Rats; Rats, Inbred Strains; Tyrosine - analogs & derivatives; Tyrosine - chemistry
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx8000835

Myeloperoxidase (MPO), secreted by activated neutrophils and macrophages at the site of inflammation, may be implicated in the oxidation of protein/lipoprotein during the development of cardiovascular diseases. Flavonoids have been suggested to act as antioxidative and anti-inflammatory agents in vivo; however, their molecular actions have not yet been fully understood. In this study, we examined the molecular basis of the inhibitory effects of dietary flavonoids, such as quercetin, and their metabolites on the catalytic reaction of MPO using a combination of biological assays and theoretical calculation studies. Immunohistochemical staining showed that a quercetin metabolite was colocalized with macrophages, MPO, and dityrosine, an MPO-derived oxidation product of tyrosine, in human atherosclerotic aorta. Quercetin and the plasma metabolites inhibited the formation of dityrosine catalyzed by the MPO enzyme and HL-60 cells in a dose-dependent manner. Spectrometric analysis indicated that quercetin might act as a cosubstrate of MPO resulting in the formation of the oxidized quercetin. Quantitative structure−activity relationship studies showed that the inhibitory actions of flavonoids strongly depended not only on radical scavenging activity but also on hydrophobicity (log P). The requirement of a set of hydroxyl groups at the 3, 5, and 4′-positions and C2−C3 double bond was suggested for the inhibitory effect. The binding of quercetin and the metabolites to a hydrophobic region at the entrance to the distal heme pocket of MPO was also proposed by a computer docking simulation. The current study provides the structure−activity relationships for flavonoids as the anti-inflammatory dietary constituents targeting the MPO-derived oxidative reactions in vivo.