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Cytochromes P450 mediated metabolism of 7- hydroxyflavone

BackgroundFlavonoids are a large group of compounds that people ingest on a daily basis byconsuming fruits and vegetables. Biological effects of these xenobiotics have been extensively studiedin vitro. Although results of in vitro studies are promising, due to low bioavailability these compoundsoften do not demonstrate their pharmacological potential in vivo. Cytochromes P450 are the mostsignificant enzymes for drug metabolism and metabolic fate of flavonoids is still poorlyunderstood.MethodsHuman liver microsomes and recombinant cytochrome P450 enzymes were used inexperiments. Metabolism was monitored by liquid chromatography coupled with mass spectrometry(electron spray ionization, time-of- flight detection). Metabolites were identified based on accuratemolecular mass data and retention time compared to standard and quantified by diode arraydetector.ResultsIncubations with recombinant enzymes revealed that CYP1A2, CYP2D6 and CYP3A4 areisozymes involved in metabolism of 7-hydroxyflavone and aromatic hydroxylation yielding6, 7-dihydroxyflavone was major metabolic pathway observed. Kinetic data suggest major role ofCYP1A2 catalyzing this reaction. Observed catalytic efficiencies were 1.5 +/- 0.3x10-6 min-1 M-1 forCYP1A2, 0.06 +/- 0.01x10-6 min-1 M-1 for CYP 2D6 and 0.05 +/- 0.02x10-6 min-1 M-1 forCYP3A4.ConclusionThis data will improve understanding of pharmacokinetics of flavonoids, helpingovercome low bioavailability observed in vivo.

7-hydroxyflavone, metabolism, cytochromes P450

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