Use of Isoform-Specific UGT Metabolism to Determine and Describe Rates and Profiles of Glucuronidation of Wogonin and Oroxylin A by Human Liver and Intestinal Microsomes

Zhou, Qiong; Zheng, Zhijie; Xia, Bao‐Hui; Tang, Lan; Lv, Chang; Liu, Wei; Liu, Zhongqiu; Hu, Ming

doi:10.1007/s11095-010-0148-0

Cited by 37 publications

(35 citation statements)

References 32 publications

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“…It has been reported that isoflavonoids, including calycosin, can be metabolized by multiple UGT enzymes (Tang et al, 2009;Ruan and Yan, 2014), and the rates and profiles of metabolism by individual UGT enzymes are different. Distribution of these enzymes in RLMs and RIMs are diverse and the rates and profiles of isoflavonoids glucuronidation in microsomes are determined by UGT enzymes (Zhou et al, 2010), which could explain why the profile of CG glucuronidation in RIMs was different from that of calycosin glucuronidation in RLMs and RIMs and of CG glucuronidation in RLMs. Although the liver is the main metabolic organ and several studies have focused on calycosin metabolism at this site (Ruan et al, 2015), our results indicate that, as the first site of metabolism after oral administration, more attention should be paid to the importance and characteristics of metabolism of calycosin and CG in the intestine.…”

Section: Discussionmentioning

confidence: 99%

SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O-β-D-Glucoside in Rats

Shi

Zheng

et al. 2016

Drug Metabolism and Disposition

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Hydrolysis by lactase-phloridzin hydrolase (LPH) is the first and critical step in the absorption of isoflavonoid glucosides. However, the absorption characteristics of calycosin-7-O-b-D-glucoside (CG) slightly differ from other isoflavonoid glucosides. In this study, we used the rat intestinal perfusion model and performed pharmacokinetic studies and in vitro experiments to determine the factors influencing CG absorption and disposition. After oral administration of isoflavonoid glucosides, LPH was found to play minimal or no role on the hydrolysis of CG, in contrast to that of daidzin. CG was mainly transported into the small intestinal cells by sodium-dependent glucose transporter 1 (SGLT-1) as intact. This pathway could be the main mechanism underlying the high permeability of CG in the small intestine. CG was likely to be hydrolyzed in enterocytes to its aglycone calycosin by broad-specific b-glucuronides (BSbG) and glucocerebrosidase or rapidly metabolized. Calycosin was also rapidly and extensively metabolized to 39-glucuronide in the enterocytes and liver, and the glucuronidation rates of calycosin and CG were much higher in the former. The metabolites were also transported into lumen by breast cancer resistance protein and multidrug resistance-associated protein 2. In conclusion, the enterocytes could be an important site for CG absorption, deglycosylation, and metabolism in rats. This study could contribute to the theoretical foundation and mechanism of absorption and disposition of flavonoid compounds.

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Section: Discussionmentioning

confidence: 99%

SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O-β-D-Glucoside in Rats

Shi

Zheng

et al. 2016

Drug Metabolism and Disposition

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“…In the extrahepatic organs, UGT 1A8 and UGT 1A10 are expressed in the gastrointestinal tract (41,42). Based on previous investigations on B from us and others (27,43), UGT 1A8 and UGT 1A10 as well as HIM and RIS9 were chosen as subcellular fractions to investigate the intestinal glucuronidation of W and OA and compared with that of B. Zhou et al demonstrated that UGT1A8 and UGT1A10 contributed to the intestinal glucuronidation of W and OA (43). However, different kinetic profiles were observed in their study.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Intestinal Absorption and Disposition of Structurally Similar Bioactive Flavones in Radix Scutellariae

Zhang

Zhou

et al. 2011

AAPS J

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Abstract. Radix Scutellariae is a commonly used herbal medicine. Baicalein, wogonin, and oroxylin A are three major bioactive flavones in Radix Scutellariae and share similar chemical structures. The intestinal absorption and disposition of baicalein have been systematically investigated by our group before. In this study, the intestinal absorption and disposition of wogonin and oroxylin A were further explored and compared with the profiles of baicalein to find potential structure-activity relationship. Absorptive models including Caco-2 cell monolayer model and rat in situ single-pass intestinal perfusion model as well as in vitro enzymatic kinetic study were employed in the current study. The absorption of baicalein, wogonin, and oroxylin A were favorable with wogonin showing the highest permeability based on two absorptive models. However, three flavones underwent a fast and extensive phase II metabolism. The intestinal metabolism of three flavones exhibited species difference between human and rat. Oroxylin A demonstrated the highest intrinsic clearance of glucuronidation among three flavones. The multidrug resistance proteins might be involved in the efflux of their intracellularly formed conjugated metabolites. The pathway of intestinal absorption and disposition of B, W, and OA was similar. However, the extent of permeability and metabolism was different among three flavones which might be due to the number and position of the hydroxyl group.

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“…The UGT isoforms involved in the metabolic elimination of wogonin have been identified. UGT1A9 was regarded as the main UGT isoform involved in the glucuronidation of wogonin in the liver, and UGT1A10 was the major UGT isoform responsible for wogonin's glucuronidation in the intestine 17 . All these information indicated the possibly good interaction between wogonin and UGT1A9.…”

Section: Discussionmentioning

confidence: 99%

Probe substrate and enzyme source-dependent inhibition of UDP-glucuronosyltransferase (UGT) 1A9 by wogonin

Gao¹,

Xie²,

T³

et al. 2013

Afr H. Sci.

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Background: Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. Objective: To evaluate the inhibition potential of wogonin (an important flavonoid isolated from the root of Scutellaria baicalensis) towards one of the most important phase II DMEs, UDP-glucuronosyltransferase (UGT) 1A9. Methods: Both recombinant UGT1A9-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and human liver microsomes (HLMs)-catalyzed propofol glucuronidation reaction were used as two different probe reactions. Results: Wogonin noncompetitively inhibited recombinant UGT1A9-catalyzed 4-MU glucuronidation, and exerted competitive inhibition towards HLMs-catalyzed propofol glucuronidation. The inhibition kinetic parameters (K i ) were calculated to be 3.2 µM and 52.0µM, respectively. Conclusion: Necessary monitoring was needed when wogonin was co-administered with the clinical drugs mainly undergoing UGT1A9-mediated glucuronidation elimination. Additionally, probe reactions-dependent inhibition of wogonin towards the activity of UGT1A9 should be paid attention when translating these in vitro data into in vivo situation.

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Use of Isoform-Specific UGT Metabolism to Determine and Describe Rates and Profiles of Glucuronidation of Wogonin and Oroxylin A by Human Liver and Intestinal Microsomes

Cited by 37 publications

References 32 publications

SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O-β-D-Glucoside in Rats

SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O-β-D-Glucoside in Rats

Comparison of Intestinal Absorption and Disposition of Structurally Similar Bioactive Flavones in Radix Scutellariae

Probe substrate and enzyme source-dependent inhibition of UDP-glucuronosyltransferase (UGT) 1A9 by wogonin

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