Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

Qian, Zhang; Cao, Yun‐Feng; Ran, Ruixue; Li, Rongshan; Wu, Xue; Dong, Peipei; Zhang, Yanyan; Hu, Cui-Min; Wang, Weiming

doi:10.1002/ptr.5496

Cited by 18 publications

(16 citation statements)

References 21 publications

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“…100 µM of atractylenolide I was demonstrated to inhibit nearly 100% of 4-methylumbelliferone metabolism in recombinantly expressed UGT2B7 isoform, with negligible inhibition toward other UGTs (UGT1A1, UGT1A3, UGT1A6, and UGT1A9). 31 This was confirmed with in-house data (not shown), revealing a 80.7% ± 0.2% inhibition of gemfibrozil metabolism in recombinantly expressed UGT2B7 (0.5 mL/mg protein) in the presence of 60 µM atractylenolide I (n = 3). Examples of activity-activity correlations between UGT2B isoforms does not necessarily imply a lack of substrate selectivity toward those UGTs but may indicate a certain degree of co-regulation in the expression.…”

Section: Discussionsupporting

confidence: 80%

“…The ontogeny of UGT2B4 was established using gemfibrozil co‐incubated with atractylenolide I, used as a UGT2B7 inhibitor. 100 µM of atractylenolide I was demonstrated to inhibit nearly 100% of 4‐methylumbelliferone metabolism in recombinantly expressed UGT2B7 isoform, with negligible inhibition toward other UGTs (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) . This was confirmed with in‐house data (not shown), revealing a 80.7% ± 0.2% inhibition of gemfibrozil metabolism in recombinantly expressed UGT2B7 (0.5 mL/mg protein) in the presence of 60 µM atractylenolide I (n = 3).…”

Section: Discussionsupporting

confidence: 75%

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Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

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Qiu

Collier

et al. 2019

The Journal of Clinical Pharma

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An understanding of the postnatal development of hepatic UDP‐glucuronosyltransferase (UGT) enzymes is required for accurate prediction of the age‐dependent changes in pharmacokinetics of many drugs used in children. However, the maturation rate of hepatic UGT isoforms remains a major knowledge gap. This study aimed to establish the age‐associated changes in glucuronidation activity of 10 major hepatic UGT isoforms in humans, namely, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17. Human liver microsomes from pediatric and adult donors were incubated under optimized incubation conditions to assess the activity rates of hepatic UGT isoforms using a panel of 19 in vitro UGT probe substrates and clinically used drugs. Statistically strong correlations of glucuronidation activities allowed the ontogeny of UGT1A1, UGT1A4, UGT2B7, UGT2B10, and UGT2B15 to be established using multiple selective UGT substrates and matched human liver microsome samples. The postnatal development of hepatic UGTs is isoform‐dependent using either individual or cross‐correlated selective isoform substrates. Maximal adult activity was reached at different times ranging from within a month (UGT1A1, UGT2B4, UGT2B7, UGT2B10, and UGT2B15), during infancy (UGT1A3, UGT1A4, and UGT1A9), to adolescence (UGT1A6 and UGT2B17). This study provides an extensive characterization of the postnatal ontogeny profiles of hepatic UGT enzymes that are instrumental for predicting drug disposition via in vitro–in vivo extrapolation algorithms and verifying pharmacokinetic predictions against in vivo observations via pediatric physiologically based pharmacokinetic modeling in pediatric patients.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 75%

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Badée

Qiu

Collier

et al. 2019

The Journal of Clinical Pharma

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“…Molecules 2016, 21, 1616 3 of 8 [13] and sorafenib [14] can disturb the activity of UGT1A1, resulting in the inhibition of bilirubin gulucuronidation; atractylenolide I and III have been proven to specifically inhibit UGT2B7, thus affecting drugs undergoing UGT2B7-catalyzed metabolism [15].…”

Section: Comparison Of Inhibition Effect Of Ast and Cagmentioning

confidence: 99%

“…The in vitro incubation experiment was carried out according to previously literature [15]. In brief, a typical 200 µL incubation mixture contained various recombinant UGT isoforms, 5 mM UDPGA, 5 mM MgCl 2 , 50 mM Tris-HCl buffer (pH = 7.4), and various concentrations of 4-MU.…”

Section: Inhibition Of Ugt Activity Assaymentioning

confidence: 99%

“…For example, fluconazole itself is not metabolized by UGT but alter pharmacokinetic parameters of co-administrated zidovudine in AIDS patients, because the glucuronidation of zidovudine by UGT2B7 is strongly inhibited by fluconazole [12]; indinavir [13] and sorafenib [14] can disturb the activity of UGT1A1, resulting in the inhibition of bilirubin gulucuronidation; atractylenolide I and III have been proven to specifically inhibit UGT2B7, thus affecting drugs undergoing UGT2B7-catalyzed metabolism [15].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

Ran

Zhang

et al. 2016

Molecules

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As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 µM for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC 50 of 0.84 µM and 11.28 µM for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver-Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver-Burk plot versus the concentrations of CAG, the inhibition constant (Ki) was calculated to be 0.034 µM and 20.98 µM for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1 > [I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), it was successfully predicted here that an in vivo herb-drug interaction between AST/CAG and drugs mainly undergoing UGT1A8-or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 µM and 20.98 µM, respectively.

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Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin

et al. 2016

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Arctiin is the major pharmacological ingredient of Fructus Arctii, and arctigenin is the metabolite of arctiin formed via the catalysis of human intestinal bacteria. The present study aims to investigate the inhibition profile of arctiin and arctigenin on important phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs), indicating the possible herb-drug interaction. In vitro screening experiment showed that 100 μM of arctiin and arctigenin inhibited the activity of UGT1A3, 1A9, 2B7, and 2B15. Homology modeling-based in silico docking of arctiin and arctigenin into the activity cavity of UGT2B15 showed that hydrogen bonds and hydrophobic interactions contributed to the strong binding free energy of arctiin (-8.14 kcal/mol) and arctigenin (-8.43 kcal/mol) with UGT2B15. Inhibition kinetics study showed that arctiin and arctigenin exerted competitive and noncompetitive inhibition toward UGT2B15, respectively. The inhibition kinetic parameters (Ki ) were calculated to be 16.0 and 76.7 μM for the inhibition of UGT2B15 by arctiin and arctigenin, respectively. Based on the plasma concentration of arctiin and arctigenin after administration of 100 mg/kg of arctiin, the [I]/Ki values were calculated to be 0.3 and 0.007 for arctiin and arctigenin, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), arctiin might induce drug-drug interaction with medium possibility. Based on these results, clinical monitoring the utilization of Fructus Arctii is very important and necessary. Copyright © 2016 John Wiley & Sons, Ltd.

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Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

Cited by 18 publications

References 21 publications

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Characterization of the Ontogeny of Hepatic UDP‐Glucuronosyltransferase Enzymes Based on Glucuronidation Activity Measured in Human Liver Microsomes

Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms

Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin

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