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

The inhibitory effect of a series of novel structurally related compou nds on the human UDP-glucuronosyltransferase UGT16 stably expressed i n a V79 cell line was investigated. The inhibitors contain a lipophili c 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 su bstrate were determined. The best inhibitor of the series, D-DPMSU, ha d an IC50 of 39 mu M in the assay conditions. Low K-i values were foun d toward both UDP-glucuronic acid and 4-methylumbelliferone (17 and 21 mu M, respectively). The inhibition was competitive toward both subst rates. A similar strong and competitive inhibitory effect was observed with two other inhibitors, DHPASU and DHPASiU. Another compound, D-DP ASiU, showed a pure competitive inhibition towards UDP-glucuronic acid , but a non-competitive inhibition towards the acceptor substrate. The se data and the optimization of the structures of the inhibitors by mo lecular modeling suggest that D-DPMSU and DHPASiU compounds may be tra nsition state analog inhibitors of the recombinant UGT16 enzyme.