Oxidation and rearrangements of flavanones by mammalian cytochrome P450.
To clarify the metabolic pathways of flavanones in mammals, the metabolism of (+/-)-flavanone and (+/-)-4'-methoxyflavanone by rat liver microsomes and recombinant human P450s in which structural changes are readily identifiable were examined. The beta-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent formation of flavone plus (+/-)-2,3-trans-flavanonol and of 4'-methoxyflavone plus (+/-)-2,3-trans-4'-methoxyflavanonol, respectively, by rat liver microsomes was observed. The same metabolites were generated by recombinant human P450s in addition to the formation of isoflavone from (+/-)-flavanone. The kinetic isotope effects in these reactions were examined using deuterated (+/-)-flavanone and (+/-)-4'-methoxyflavanone. There was a strong isotope effect in the production of flavanonols, but the isotope effect in the production of flavones was small. The results indicated that the P450-mediated conversion of (+/-)-flavanone and of (+/-)-4'-methoxyflavanone to the corresponding metabolites proceeded via abstraction of a hydrogen radical from the C-2- or C-3-position of the flavanone skeleton. The antioxidant properties of flavanone and its metabolites were examined by measuring superoxide-scavenging activity in a xanthine-xanthine oxidase-cytochrome c system. (+/-)-2,3-trans-Flavanonol had higher activity than that of other flavonoids. Flavanones are metabolized by mammalian P450s, providing important information relevant to the metabolism and pharmacological action of dietary flavanones.
Kagawa
H
H
Department of Organic Synthesis, School of Pharmaceutical Sciences, Kitasato University, 9-1, Shirokane 5-chome, Minato-ku, Tokyo 108-8641, Japan. kagawah@pharm.kitasato-u.ac.jp
Takahashi
T
T
Ohta
S
S
Harigaya
Y
Y
D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D044950:Flavanones / Q000737:chemistry*; D047309:Flavones / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007554:Isotopes / Q000737:chemistry; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D009249:NADP / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry
D000975:Antioxidants; D044950:Flavanones; D047309:Flavones; D007554:Isotopes; D011994:Recombinant Proteins; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen