Oxidation and rearrangements of flavanones by mammalian cytochrome P450

1. 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. 2. The β-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. 3. The same metabolites were generated by recombinant human P450s in addition to the formation of isoflavone from (±)- flavanone. 4. 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. 5. 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. 6. Flavanones are metabolized by mammalian P450s, providing important information relevant to the metabolism and pharmacological action of dietary flavanones.