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

Hong, Xin; Xia, Yangliu; Hou, Jie; Wang, Ping; He, Wei; Yang, Ling; Ge, Guang-Bo; Xu, Wei

doi:10.1111/jphp.12483

Cited by 13 publications

(14 citation statements)

References 31 publications

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“…And in intestine and liver, AG could be extensively metabolized to one mono-glucuronide and undergo a first-pass metabolism during the absorption process. Therefore, elimination ability is strong (Gao et al, 2014a,b; Xin et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…The substrates remaining of AG in four species liver microsomes were human (62 ± 6.36%) > beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). It was reported that AG could be metabolized to one mono-glucuronide in human liver microsomes (Xin et al, 2015). And AG could be metabolized to arctigenic acid and arctigenin-4′- O -glucuronide by the first pass effect in intestine of rats (Gao et al, 2014a,b).…”

Section: Discussionmentioning

confidence: 99%

“…Although numerous studies have discovered multiple promising pharmacological and extensively therapeutic activities of AG, systematic evaluation of its pharmacokinetic characteristics were still limited (Xin et al, 2015), although there are some ADME studies of this compound in vivo and in vitro . It is reported that AG can be metabolized to be arctigenic acid and arctigenin-4′- O -glucuronide in rats’ plasma by oral administration (Gao et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

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Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

Ren

et al. 2017

Front. Pharmacol.

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Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h), a high absorption degree (absolute bioavailability > 100%), and a strong elimination ability (t1/2 < 2 h). The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak) and wide (detectable in almost all tissues and organs). The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min). The percentages of AG remaining in four species’ liver microsomes were human (62 ± 6.36%) > beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

Ren

et al. 2017

Front. Pharmacol.

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“…Both arctiin and arctigenin were demonstrated to exert strong inhibitory effects on the activity of UGT1A3, 1A9, 2B7, and 2B15. UGT1A3, 1A9, and 2B7 were involved in the metabolism of arctigenin (Xin et al , ), possibly explaining why arctiin and arctigenin exhibited strong inhibition toward these three UGT isoforms. It should be noted that UGT2B15 is not the UGT isoform participating in the metabolism of arctigenin, indicating poor substrate property of arctigenin for UGT2B15.…”

Section: Discussionmentioning

confidence: 99%

“…The recent study performed by Xin et al showed that UGT1A9, 2B7, and 2B17 mainly contributed to the metabolism of arctigenin in the liver, and UGT2B7 and UGT2B17 mainly contributed to the metabolism of arctigenin in the intestine (Xin et al , ), indicating the good interaction between arctigenin‐like structure and the activity cavity of several UGT isoforms. Therefore, the recent study aims to investigate the inhibition of arctiin and arctigenin on the activity of UGT isoforms.…”

Section: Introductionmentioning

confidence: 99%

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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Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

et al. 2018

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Bisdemethoxycurcumin (BDMC) was a natural curcuminoid with many bioactivities present in turmeric (Curcuma longa L.). However, the disposition mechanisms of BDMC via uridine 5 0 -diphospho-glucuronosyltransferase (UGT) metabolism still remain unclear. Therefore, we aimed to determine the potential efflux transporters for the excretion of BDMC-O-glucuronide. Herein, chemical inhibition assays (Ko143, MK571, dipyridamole, and leukotriene C4) and biological inhibition experiments including stable knocked-down of breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRPs) transporters were both performed in a HeLa cell line stably overexpressing UGT1A1 established previously. The results indicated that Ko143 (5 and 20 μM) caused a marked reduction in excretion rate (18.4-55.6%) and elevation of intracellular BDMC-O-glucuronide (28.8-48.1%), whereas MK-571 (5 and 20 μM) resulted in a significant decrease in excretion rate (6.2-61.6%) and increase of intracellular BDMC-O-glucuronide (maximal 27.1-32.6%). Furthermore, shRNAmediated silencing of BCRP transporter led to a marked reduction in the excretion rate (21.1-36.9%) and an obvious elevation of intracellular glucuronide (24.9%). Similar results were observed when MRP1 was partially silenced. In addition, MRP3 and MRP4 silencing both displayed no obvious changes on the excretion rate and intracellular levels of glucuronide. In conclusion, chemical inhibition and gene silencing results both indicated that generated BDMC-O-glucoside were excreted primarily by the BCRP and MRP1 transporters.

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

Abstract: UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4'-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM.

Cited by 13 publications

References 31 publications

Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

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

Efflux excretion of bisdemethoxycurcumin‐O‐glucuronide in UGT1A1‐overexpressing HeLa cells: Identification of breast cancer resistance protein (BCRP) and multidrug resistance‐associated proteins 1 (MRP1) as the glucuronide transporters

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