Glucuronidation of 3′-azido-3′-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase: Significance of nucleoside hydrophobicity and inhibition by xenobiotics

Abstract

The enzymatic glucuronidation of 3′-azido-3′-deoxythymidine (AZT) catalyzed by human liver microsomal UDP-glucuronosyltransferase (EC 2.4.1.17, UDPGT) was inhibited by a number of nucleoside analogs. The inhibitory potency of these nucleoside analogs correlated with their hydrophobicity ( r 2 = 0.90, N = 13). Since similar results were obtained with solubilized UDPGT ( r 2 = 0.87, N = 7), the affinity of the nucleosides for UDPGT was probably being assessed rather than the ability of the compounds to access the membrane-bound enzyme. Three homologous inhibitors, 3′-azido-2′,3′-dideoxyuridine (AzddU), 5-ethyl-AzddU, and 5-propyl-AzddU, were also studied as substrates of UDPGT. The substrate efficiency ( V max/ K m) of these three compounds and AZT also correlated with their hydrophobicity ( r 2 = 0.94). Sixteen drugs that are structurally unrelated to nucleosides also inhibited the glucuronidation of AZT. The mechanism of inhibition was competitive for seven compounds tested. K i , values were estimated from Dixon plots for nine other less soluble inhibitors; their mechanism of inhibition was assumed to be competitive. Since the peak physiological drug concentrations of the tested inhibitors are considerably less than their K i values, none of these compounds are expected to strongly inhibit AZT glucuronidation in humans. However, the rank order of these drugs with respect to their inhibitory potential is probenecid > chrloramphenicol > naproxen > phenylbutazone > other drugs tested.