Mechanism of inhibition of rat liver bilirubin UDP-glucuronosyltransferase by triphenylalkyl derivatives.
A series of potent and competitive inhibitors of UDP-glucuronosyltransferase derived from 7,7,7-triphenylheptanoic acid has been synthesized in order to probe the active site of the isozyme involved in the glucuronidation of the endogenous toxic compound, bilirubin IX alpha. Like triphenylalkylcarboxylic acids, triphenyl alcohols were found to be very effective competitive inhibitors of the reaction (Ki 12 to 180 microM). Superimposition of the best inhibitors with bilirubin by computer modeling showed a marked spatial similarity, which accounts for the observed competitive-type inhibition. The bulky triphenylmethyl moiety of the inhibitor superimposed well on the part of the bilirubin molecule containing three of the four pyrrole rings. In agreement, substitution of the triphenylmethyl moiety by planar structures such as fluorenyl or indenyl rings completely suppressed the inhibition. In addition, the weak inhibition exerted by the shortest carboxylic acids could be related to the higher acidity of these molecules. The inhibition potency depended on the acidity of the molecules; the more acidic, the less inhibitory, suggesting that the presence of a negative charge on the inhibitor molecule prevents bilirubin glucuronidation. Based on these results, a reaction mechanism for bilirubin glucuronidation is postulated.
Said
M
M
University Mohamed I, Département de Biologie, Oujda, Morocco.
Battaglia
E
E
Elass
A
A
Cano
V
V
Ziegler
J C
JC
Cartier
A
A
Livertoux
M H
MH
Vergoten
G
G
Fournel-Gigleux
S
S
Magdalou
J
J
D000818:Animals; D001663:Bilirubin / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar
C110242:7,7,7-triphenylheptanoic acid; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase; D001663:Bilirubin