title: Effect of chrysin and natural coumarins on UGT1A1 and 1A6 activities in rat and human hepatocytes in primary culture.
abstract: Flavonoids and coumarins are naturally occurring compounds that are widely distributed in vegetables and have a broad pharmacological activity. Inducibility of UDP-glucuronosyltransferases (UGTs) by xenobiotics is well documented and can be considered beneficial for health. In particular, UGT1A1-dependent bilirubin conjugation plays a critical role in the detoxification of neurotoxic bilirubin and phenobarbital-mediated UGT1A1 induction therapy is commonly used in the treatment of unconjugated hyperbilirubinemic diseases such as Crigler-Najjar type II disease. In the present study, the effects of the flavone chrysin and six natural coumarins isolated from various Rutaceous plants on UGT1A6-dependent P-nitrophenol and/or UGT1A1-dependent bilirubin glucuronoconjugation activities were evaluated in cultured rat and human hepatocytes and compared to those of the prototypical UGT1A inducers beta-naphthoflavone, phenobarbital and clofibric acid. After 3 days of treatment at a concentration of 25 microM, the pyranocoumarins avicennin and CIS-avicennol, and the furocoumarins bergapten and imperatorin, increased by 2-fold UGT1A1-dependent activity, equivalent to the increases obtained with chrysin at 25 microM, whereas in the presence of the simple coumarins such as coumarin or umbelliferone, UGT1A1-dependent activity was not modified. In terms of structural requirements for UGT1A1 induction, the present study suggests that the B-ring (phenyl) for chrysin and the furan or pyran rings for coumarins are essential for the biological activity.
authors.affiliation: Laboratoire de Pharmacognosie, EA 3921 Optimisation Métabolique et Cellulaire, IFR 133, UFR des Sciences Médicales et Pharmaceutiques, Besançon, France.
authors.forename: Amina
authors.initials: A
authors.lastname: Chlouchi
authors.forename: Corinne
authors.initials: C
authors.lastname: Girard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bonet
authors.forename: Catherine
authors.initials: C
authors.lastname: Viollon-Abadie
authors.forename: Bruno
authors.initials: B
authors.lastname: Heyd
authors.forename: Georges
authors.initials: G
authors.lastname: Mantion
authors.forename: Hélène
authors.initials: H
authors.lastname: Martin
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
mesh_terms: D000818:Animals; D003374:Coumarins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008517:Phytotherapy; D051381:Rats; D027821:Rutaceae; D000099148:UGT1A1 Enzyme
chemical_list: D003374:Coumarins; D005419:Flavonoids; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C043561:chrysin; C110655:UDP-glucuronosyltransferase, UGT1A6