The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors

Human uridine-5′-diphosphoglucuronosyltransferases (UGTs) are the major phase II metabolizing enzymes. In the present study, five human UGTs (UGT1A1, 1A4, 1A6, 2B7, and 2B10) were individually expressed and used to examine the inhibition IC50 values of 20 selective substrates and inhibitors of major cytochromes P450 (CYPs). The inhibition kinetics of UGT1A1 was also analyzed. The results showed that some compounds like α-naphthoflavone, paclitaxel, midazolam, cyclosporine A, and ketoconazole displayed strong inhibitions on UGT activities with their IC50 values in a range of 4.1-26 µM. Especially, the IC50 values were 4.1 ± 0.8 µM for ketoconazole in inhibiting UGT1A1-mediated β-estradiol-3-glucuronidation, and 4.9 ± 0.3 µM for paclitaxel towards UGT1A4-mediated midazolam-N-glucuronidation. Additionally, the IC50 values of bupropion, tolbutamide, and testosterone in inhibiting UGT-mediated metabolisms were similar with the Km values of respective CYPs. Some kinetic behaviours of UGTs were following Michaelis-Menten kinetics, while some were not.