title: Selective and potent inhibition of different hepatic UDP-glucuronosyltransferase activities by omega,omega,omega-triphenylalcohols and UDP derivatives.
abstract: A homologous series of omega,omega,omega-triphenylalcohols and corresponding omega,omega,omega-triphenylalkyl-UDP derivatives was synthesized and tested as inhibitors of UDP-glucuronosyltransferase (UGT) activity in rat liver microsomes, with 1-naphthol, testosterone and bilirubin as substrates. Introduction of the UDP moiety in the triphenylalcohols increased their inhibition potency markedly toward the isoforms which glucuronidate 1-naphthol and testosterone, but strongly decreased that toward bilirubin. The inhibiting potency of the UDP-derivatives increased as a function of the length of the hydrocarbon chain. The best inhibitor 7,7,7-triphenylheptyl-UDP showed an I50 of 30 and 10 microM for 1-naphthol and testosterone glucuronidation, respectively; even a 1 mM concentration of the compound had little, if any, effect on bilirubin glucuronidation. The inhibition by 7,7,7-triphenylheptyl-UDP was mixed-type toward 1-naphthol, and non competitive toward testosterone (apparent K(i) 30 microM and 1.7 microM, respectively); on the other hand, the inhibition was competitive toward the common substrate UDP-glucuronic acid (apparent K(i) 1.9-1.2 microM). In addition, 7,7,7-triphenylheptyl-UDP (0.25-0.50 mM) almost inhibited glucuronidation of 1-naphthol and testosterone catalyzed by the recombinant rat liver UGT-2B1 and human liver UGT-1A1, whose cDNA has been expressed in V79 cells. In conclusion, the data indicate that 7,7,7-triphenyheptyl-UDP interacted competitively with the UDP binding site of UGT. The results also indicate that it is possible to design transition state analogue inhibitors with specificity for different UGT forms.
authors.affiliation: Centre du Médicament, URA CNRS n.597, Nancy, France.
authors.forename: M
authors.initials: M
authors.lastname: Said
authors.forename: D
authors.initials: D
authors.lastname: Noort
authors.forename: J
authors.initials: J
authors.lastname: Magdalou
authors.forename: J C
authors.initials: JC
authors.lastname: Ziegler
authors.forename: G A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: J H
authors.initials: JH
authors.lastname: van Boom
authors.forename: G J
authors.initials: GJ
authors.lastname: Mulder
authors.forename: G
authors.initials: G
authors.lastname: Siest
mesh_terms: D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D001667:Binding, Competitive; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D009284:Naphthols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000438:Alcohols; D005965:Glucuronates; D007527:Isoenzymes; D009284:Naphthols; C029350:1-naphthol; D013739:Testosterone; D014530:Uridine Diphosphate; D014453:Glucuronosyltransferase; D001663:Bilirubin