Identification and Characterization of Human UDP-glucuronosyltransferases Responsible for the Glucuronidation of Fraxetin

Xia, Yangliu; Liang, Sisi; Zhu, Liangliang; Ge, Guang-Bo; He, Guiyuan; Ning, Jing; Lv, Xia; Ma, Xiaochi; Yang, Ling; Yang, Shengli

doi:10.2133/dmpk.dmpk-13-rg-059

Cited by 27 publications

(15 citation statements)

References 22 publications

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“…In the sugar moiety, the G1 protons and carbons exhibited characteristic chemical shifts near 5 and 100 ppm, whereas the G6 carbon (‐COOH) showed chemical shifts of approximately 170 ppm. In addition, the β ‐configuration of the glucuronic acid moiety was confirmed by the coupling constant of the anomeric proton (δ5.01, J = 7.0 Hz), which agreed well with previous reports regarding the O‐glucuronides [19]. All these evidence clearly demonstrated that the glucuronidation site was located at the C‐4′ phenolic group of AR and the glucuronide was identified as AR‐4′‐O‐glucuronide (Figure ).…”

Section: Resultssupporting

confidence: 90%

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin

Hong

Xia

Hou

et al. 2015

Journal of Pharmacy and Pharmacology

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Section: Resultssupporting

confidence: 90%

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin

Hong

Xia

Hou

et al. 2015

Journal of Pharmacy and Pharmacology

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“…These findings suggest that the C-7 phenol group should receive more attention in further structure modifications aimed toward increasing the metabolic stability of 6,7-DHCs. To date, UGT1A6 and 1A9 have been identified as the major enzymes catalyzing C-7 glucuronidation of coumarins, including 4-MU, daphnetin, and fraxetin (Tukey and Strassburg, 2000;Liang et al, 2010;Xia et al, 2014). In our study, UGT1A6 and UGT1A9 were also effective in 7-O-glucuronidation of 6,7-DHCs.…”

Section: Discussionsupporting

confidence: 51%

“…For example, 4-methylumbelliferone (Tukey and Strassburg, 2000), daphnetin , and fraxetin (Xia et al, 2014) are quickly metabolized by various human UDP-glucuronosyltransferases (UGTs) with high hepatic clearance. Although most UGT1A isoforms are involved, previous studies demonstrated that UGT1A6 and UGT1A9 were the major enzymes catalyzing 7-O-glucuronidation and 8-Oglucuronidation of 7,8-DHCs Xia et al, 2014). However, the glucuronidation positions of 6,7-DHCs and the involved human enzymes have yet to be characterized, which would be necessary before making structural modifications to improve their metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins

Xia

Wang

et al. 2015

Drug Metab Dispos

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Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacologic activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human UDPglucuronosyltransferase (UGT) enzymes remain unclear. This study was aimed at exploring the structure-glucuronidation relationship of esculetin and its C-4 derivatives, including 4-methyl esculetin, 4-phenyl esculetin, and 4-hydroxymethyl esculetin as well as 4-acetic acid esculetin. It was achieved by identifying the main human UGTs responsible for the different reactions and by careful characterization of the reactions kinetics. These catechols, with the exception of 4-acetic acid esculetin, are selectively metabolized to the corresponding 7-O-glucuronides. UGT1A6 and UGT1A9 are the two major UGTs involved in the 7-O-glucuronidation of 4-methyl esculetin and esculetin. UGT1A6 was the major contributor for 7-O-glucuronidation of 4-hydroxymethyl esculetin, and UGT1A9 played a significant role in the 7-O-glucuronidation of 4-phenyl esculetin. The results of the kinetic analyses revealed that the K m values of the compounds, in both UGT1A9 and human liver microsomes, decreased with increasing hydrophobicity of the C-4 substitutions. The outcome of this was that C-4 hydrophobic and hydrophilic groups on 6,7-dihydroxycoumarin exhibited contrasting effects on UGT affinity. All of these findings provide helpful guidance for further structural modification of 6,7-dihydroxycoumarins with improved metabolic stability.

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“…UGTs are a superfamily of isoforms known to have distinct, but overlapping, substrate selectivities, yet the underlying mechanism governing the observed selectivity is not completely understood (Radominska-Pandya, et al, 1999;Sorich, et al, 2004;Miners, et al, 2010;Wu et al, 2012). Generally, UGT1A9 has been shown to prefer sterically hindered nucleophiles bound to an aromatic ring (e.g., propofol; Lee et al, 2003;Sorich et al, 2004;Xia et al, 2014), though this does not fit the chemical structure of EPA. Additionally, UGT1A9 is known to glucuronidate N-hydroxylated arylamines and by extension was found to be the major isoform responsible for O-glucuronidation of benzamidoxime (Fröhlich et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans

Boer

Young-Sciame

Lee

et al. 2016

Drug Metabolism and Disposition

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Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.

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Identification and Characterization of Human UDP-glucuronosyltransferases Responsible for the Glucuronidation of Fraxetin

Cited by 27 publications

References 22 publications

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin

Structural Modifications at the C-4 Position Strongly Affect the Glucuronidation of 6,7-Dihydroxycoumarins

Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans

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