title: Characterization of a new class of inhibitors of the recombinant human liver UDP-glucuronosyltransferase, UGT1*6.
abstract: The inhibitory effect of a series of novel structurally related compounds on the human UDP-glucuronosyltransferase UGT1*6 stably expressed in a V79 cell line was investigated. The inhibitors contain a lipophilic N-acyl phenylaminoalcohol residue and a uridine moiety connected by a spacer varying for each compound. The effects of these compounds on the glucuronidation reaction measured with 4-methylumbelliferone as substrate were determined. The best inhibitor of the series, D-DPMSU, had an IC50 of 39 microM in the assay conditions. Low Ki values were found toward both UDP-glucuronic acid and 4-methylumbelliferone (17 and 21 microM, respectively). The inhibition was competitive toward both substrates. A similar strong and competitive inhibitory effect was observed with two other inhibitors, DHPASU and DHPASiU. Another compound, D-DPASiU, showed a pure competitive inhibition towards UDP-glucuronic acid, but a non-competitive inhibition towards the acceptor substrate. These data and the optimization of the structures of the inhibitors by molecular modeling suggest that D-DPMSU and DHPASiU compounds may be transition state analog inhibitors of the recombinant UGT1*6 enzyme.
authors: Centre du Médicament, URA CNRS 597, Faculté des Sciences Pharmaceutiques et Biologiques, Nancy, France.
authors: E
authors: E
authors: Battaglia
authors: A
authors: A
authors: Elass
authors: R R
authors: RR
authors: Drake
authors: P
authors: P
authors: Paul
authors: S
authors: S
authors: Treat
authors: J
authors: J
authors: Magdalou
authors: S
authors: S
authors: Fournel-Gigleux
authors: G
authors: G
authors: Siest
authors: G
authors: G
authors: Vergoten
authors: R
authors: R
authors: Lester
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006923:Hymecromone / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008958:Models, Molecular; D009284:Naphthols / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D009284:Naphthols; D011412:Propanolamines; D011994:Recombinant Proteins; D013450:Sulfones; C081648:5'-((N-(2-decanoylamino-3-hydroxy-3-phenylpropyloxycarbonyl)glycyl)amino)-5'-deoxyuridine; C081650:5'-O-(((2-decanoylamino-3-phenylpropyloxycarbonyl)amino)sulfonyl)uridine; C081649:5'-O-(((2-decanoylamino-3-hydroxy-3-phenylpropyloxycarbonyl)amino)sulfonyl)uridine; C091642:5'-O-(((2-decanoyl-amino-3-hydroxy-3-phenylpropyloxycarbonyl)amino)sulfonyl)-2',3'-O-isopropylideneuridine; C029350:1-naphthol; D006923:Hymecromone; D014453:Glucuronosyltransferase; D003857:Deoxyuridine; D014529:Uridine