CHARACTERIZATION OF A NEW CLASS OF INHIBITORS OF THE RECOMBINANT HUMAN LIVER UDP-GLUCURONOSYLTRANSFERASE, UCT1-ASTERISK-6

被引:16
作者
BATTAGLIA, E
ELASS, A
DRAKE, RR
PAUL, P
TREAT, S
MAGDALOU, J
FOURNELGIGLEUX, S
SIEST, G
VERGOTEN, G
LESTER, R
RADOMINSKA, A
机构
[1] UNIV ARKANSAS MED SCI HOSP,DEPT INTERNAL MED,LITTLE ROCK,AR 72204
[2] FAC SCI PHARMACEUT & BIOL NANCY,CTR MEDICAMENT,CNRS,URA 597,F-54000 NANCY,FRANCE
[3] UNIV SCI & TECH LILLE FLANDRES ARTOIS,F-59650 VILLENEUVE DASCQ,FRANCE
[4] UNIV ARKANSAS MED SCI HOSP,DEPT BIOCHEM & MOLEC BIOL,LITTLE ROCK,AR 72204
[5] CIBA GEIGY LTD,PHARMACEUT RES LABS,CH-4002 BASEL,SWITZERLAND
来源
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 1995年 / 1243卷 / 01期
关键词
UDP-GLUCURONOSYLTRANSFERASE; HUMAN LIVER; INHIBITORS; GLUCURONIDATION; MOLECULAR MODELING;
D O I
10.1016/0304-4165(94)00106-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M in the assay conditions. Low K-i values were found toward both UDP-glucuronic acid and 4-methylumbelliferone (17 and 21 mu M, 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.
引用
收藏
页码:9 / 14
页数:6
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