Stereoselective Metabolism of Naringenin Enantiomers in Rat Liver Microsomes: CYP3A Dependency and Species Specificity

Naringenin, a chiral flavonoid, contains a chiral center and exists as ( R )- and ( S )-enantiomers, yet its enantiomer-specific metabolism has remained largely unexplored. Herein, high-purity ( R )- and ( S )-naringenin were isolated via chiral semipreparative chromatography, and their racemization kinetics under near-physiological conditions were systematically quantified. Incubation with rat liver microsomes revealed pronounced stereoselectivity: the ( R )-enantiomer was metabolized significantly faster than the ( S )-enantiomer. Mechanistic studies identified the CYP3A subfamily as the key mediator of this stereoselectivity. Notably, this stereoselective profile was completely absent in human liver microsomes, uncovering a critical species difference. These findings provide direct evidence for enzyme-level chiral recognition in naringenin metabolism and highlight species-specific disparities in its metabolic pathway.