title: In vivo and in vitro glucuronidation of the flavonoid diosmetin in rats.
abstract: Flavonoids form an important family of compounds widely present in plants and therefore in food, sometimes as substitutes for synthetic antioxidants. Although the excretion routes of flavonoids in animals has been explored, little is known about the details of their conjugation in the xenobiotic metabolism pathway. In this study, we investigate the metabolism of diosmetin as a model compound in the rat, particularly its level in blood after treatment (100 mg/kg, po) and the presence of its glucuronide(s) in both blood and urine. We demonstrate that after po treatment of the rat, a rapid glucuronidation takes place and that diosmetin circulates as glucuronides, whereas no free diosmetin is present in blood and urine. The glucuronides formed are present in the blood plasma at a high level (approximately 10 micrograms/ml), for at least 6 hr after the treatment and the conjugates are excreted in urine. We have detected four different glucuronides in blood and characterized the two major ones after purification by a combination of MS, NMR, and UV spectroscopy: diosmetin-7,3'-diglucuronide and diosmetin-3'-glucuronide. A brief characterization of the in vitro glucuronidation of some flavonoid compounds using liver microsomal preparations suggests that this important class of natural compounds might be conjugated by a specific isoform of UDP-glucuronosyltransferase. Thus, this work brings evidence that diosmetin is rapidly glucuronoconjugated in the rat and provides an explanation for the low po bioavailability of the unchanged compound that can be generalized to this important class of natural compounds.
authors.affiliation: Division de Physico-Chimie Analytique, Institut de Recherches Servier, Suresnes, France.
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: F
authors.initials: F
authors.lastname: Meunier
authors.forename: P H
authors.initials: PH
authors.lastname: Lambert
authors.forename: P
authors.initials: P
authors.lastname: Hennig
authors.forename: D
authors.initials: D
authors.lastname: Bertin
authors.forename: B
authors.initials: B
authors.lastname: Serkiz
authors.forename: J P
authors.initials: JP
authors.lastname: Volland
mesh_terms: D000818:Animals; D004790:Enzyme Induction; D005419:Flavonoids / Q000097:blood / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D005419:Flavonoids; D005965:Glucuronates; D007527:Isoenzymes; D014453:Glucuronosyltransferase; C039602:diosmetin