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

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Liu Y, She M, Wu Z, Dai R

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

J Enzyme Inhib Med Chem. 2011 Jun;26(3):386-93. doi: 10.3109/14756366.2010.518965. Epub 2010 Oct 13.

PubMed ID

20939765 [ View in PubMed

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Abstract

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 IC(50) 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 alpha-naphthoflavone, paclitaxel, midazolam, cyclosporine A, and ketoconazole displayed strong inhibitions on UGT activities with their IC(50) values in a range of 4.1-26 microM. Especially, the IC(50) values were 4.1 +/- 0.8 microM for ketoconazole in inhibiting UGT1A1-mediated beta-estradiol-3-glucuronidation, and 4.9 +/- 0.3 microM for paclitaxel towards UGT1A4-mediated midazolam-N-glucuronidation. Additionally, the IC(50) values of bupropion, tolbutamide, and testosterone in inhibiting UGT-mediated metabolisms were similar with the K(m) values of respective CYPs. Some kinetic behaviours of UGTs were following Michaelis-Menten kinetics, while some were not.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Midazolam	UDP-glucuronosyltransferase 1-4	Protein	Humans	No	Substrate	Details