Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism.
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Nishimura Y, Maeda S, Ikushiro S, Mackenzie PI, Ishii Y, Yamada H
Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism.
Biochim Biophys Acta. 2007 Nov;1770(11):1557-66. Epub 2007 Aug 8.
- PubMed ID
- 17764847 [ View in PubMed]
- Abstract
The inhibitory effects of nucleotides and related substances on rat hepatic UDP-glucuronosyltransferase (UGT) were studied. ATP and NADP+ markedly reduced 4-methylumbelliferone (4-MU) UGT activity only when detergent-treated rat liver microsomes were used as the enzyme source. The IC50 values of adenine, ATP, NAD+ and NADP+ were estimated to be below 20 microM, whereas AMP had no inhibitory effect. From the kinetic behavior observed, these adenine-related compounds were assumed to inhibit UGT activity non-competitively without competing with either 4-MU or UDP-glucuronic acid. Among guanine, cytosine and their related nucleotides, only triphosphate nucleotides (CTP and GTP) exhibited potent UGT inhibition, although the effect of GTP was weak. Estradiol 3- and 17-glucuronidation were also inhibited by the inhibitors of 4-MU UGT. The only exception was that estradiol 17-glucuronidation activity was inhibited by AMP (IC50=31 microM). In addition, AMP antagonized the inhibitory effects of adenine, ATP, and NADP+ on 4-MU and estradiol 3- glucuronidation activities. These results suggest that (1) a number of cellular nucleotides present within the endoplasmic reticulum regulate UGT function; and (2) these substances bind to a common allosteric site on UGT to reduce catalytic function.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Adenine UDP-glucuronosyltransferase 1-1 Protein Humans UnknownInhibitorDetails