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

Gao, Chunfang; Xie, Rui; T, Ma; Yan, Wei; Liqun, Pang

doi:10.4314/ahs.v13i3.3

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…The contribution of the different UGT isoforms to drug metabolism is highly variable due to different substrate specificity and different expression levels in organs. Generally, glucuronidation studies of a compound are divided into several aspects [33], including UGT-isoform-specific metabolic fingerprint (GSMF) [34], enzyme kinetics and the evaluation of the importance of glucuronidation in the metabolism of the compounds. Previous studies showed that GL-V9 underwent an extensive metabolism in liver after administration, where it could be catalyzed by a family of UGT [35].…”

Section: Introductionmentioning

confidence: 99%

An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

et al. 2019

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GL-V9 is a prominent derivative of wogonin with a wide therapeutic spectrum and potent anti-tumor activity. The metabolism characteristics of GL-V9 remain unclear. This study aimed to clarify the metabolic pathway of GL-V9 and investigate the generation of its glucuronidation metabolites in vitro and in vivo. HPLC-UV-TripleTOF was used to identify metabolites. The main metabolite that we found was chemically synthesized and the synthetic metabolite was utilized as standard substance for the subsequent metabolism studies of GL-V9, including enzyme kinetics in liver microsomes of five different species and reaction phenotyping metabolism using 12 recombinant human UDP-glucuronosyltransferase (UGT) isoforms. Results indicated that the glucuronidation reaction occurred at C5-OH group, and 5-O-glucuronide GL-V9 is the only glucuronide metabolite and major phase II metabolite of GL-V9. Among 12 recombinant human UGTs, rUGT1A9 showed the strongest catalytic capacity for the glucuronidation reaction of GL-V9. rUGT1A7 and rUGT1A8 were also involved in the glucuronidation metabolism. Km of rUGT1A7-1A9 was 3.25 ± 0.29, 13.92 ± 1.05, and 4.72 ± 0.28 μM, respectively. In conclusion, 5-O-glucuronide GL-V9 is the dominant phase II metabolite of GL-V9 in vivo and in vitro, whose formation rate and efficiency are closely related to isoform-specific metabolism profiles and the distribution of UGTs in different tissues of different species.

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Section: Introductionmentioning

confidence: 99%

An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

et al. 2019

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“…According to the chromatogram of 4-MU, a nonselective substrate of UGT2B7, with different concentration gradients (0-1 mM), the standard curve of 4-MU under 316 nm irradiation in C18 HPLC column (4.6 × 250 mm, 5 µm, GL Science, Fukushima, Japan) at a flow rate of 1 mL/min was obtained [30][31][32][33][34][35]. Rutin, nicotifiorin, isovitexin, vitexin, HPAA, DHPAA, aucubin, and asperuloside were dissolved in DMSO.…”

Section: Hplc Assessment Of Inhibitory Effects Of Flavones Against Hu...mentioning

confidence: 99%

“…4-methylumbelliferone (4-MU) has been widely used as a non-specific substrate of UGT to determine the effect of chemicals on UGT activity [30][31][32][33][34][35]. Catalyzed by UGT, 4-MU obtains the glucuronic acid group transferred from UDPGA through a glucuronidation binding reaction.…”

Section: Introductionmentioning

confidence: 99%

Properties of Dietary Flavone Glycosides, Aglycones, and Metabolites on the Catalysis of Human Endoplasmic Reticulum Uridine Diphosphate Glucuronosyltransferase 2B7 (UGT2B7)

Xu,

Lv,

Cui

et al. 2023

Nutrients

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Flavone glycosides, their aglycones, and metabolites are the major phytochemicals in dietary intake. However, there are still many unknowns about the cellular utilization and active sites of these natural products. Uridine diphosphate glucuronosyltransferases (UGTs) in the endoplasmic reticulum have gene polymorphism distribution in the population and widely mediate the absorption and metabolism of endogenous and exogenous compounds by catalyzing the covalent addition of glucuronic acid and various lipophilic chemicals. Firstly, we found that rutin, a typical flavone O-glycoside, has a stronger UGT2B7 binding effect than its metabolites. After testing a larger number of flavonoids with different aglycones, their aglycones, and metabolites, we demonstrated that typical dietary flavone O-glycosides generally have high binding affinities towards UGT2B7 protein, but the flavone C-glycosides and the phenolic acid metabolites of flavones had no significant effect on this. With the disposition of 4-methylumbelliferone examined by HPLC assay, we determined that 10 μM rutin and nicotifiorin could significantly inhibit the activity of recombinant UGT2B7 protein, which is stronger than isovitexin, vitexin, 3-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid. In addition, in vitro experiments showed that in normal and doxorubicin-induced lipid composition, both flavone O-glycosides rutin and flavone C-glycosides isovitexin at 10 μM had no significant effect on the expression of UGT1A1, UGT2B4, UGT2B7, and UGT2B15 genes for 24 h exposure. The obtained results enrich the regulatory properties of dietary flavone glycosides, aglycones, and metabolites towards the catalysis of UGTs and will contribute to the establishment of a precise nutritional intervention system based on lipid bilayers and theories of nutrients on endoplasmic reticulum and mitochondria communication.

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Wogonin and its analogs for the prevention and treatment of cancer: A systematic review

Banik

Khatoon

Harsha

et al. 2022

Phytotherapy Research

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The medicinal plant Scutellaria baicalensis, commonly known as Chinese skullcap or Huang-Qin, has been used as a traditional medicine for several thousand years. The roots of this plant contain bioactive compounds, such as wogonin (WOG), wogonoside, baicalein, and baicalin. The aim of this article is to evaluate the therapeutic potential and mechanisms of action of WOG against different cancers. Numerous in vitro and in vivo studies have revealed that WOG exerts immense therapeutic potential against bladder cancer, breast cancer, cholangiocarcinoma, cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatic cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer by regulating various cell signaling pathways. WOG, in combination with established chemotherapeutic drugs, improves the efficacy of treatment and lowers toxicity. Nevertheless, human trials are warranted to validate these findings.Numerous preclinical studies, combined with an extensive margin of safety and no severe side effects, underscore WOG's therapeutic potential as an anticancer drug.

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

Cited by 3 publications

References 21 publications

An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

An Investigation on Glucuronidation Metabolite Identification, Isozyme Contribution, and Species Differences of GL-V9 In Vitro and In Vivo

Properties of Dietary Flavone Glycosides, Aglycones, and Metabolites on the Catalysis of Human Endoplasmic Reticulum Uridine Diphosphate Glucuronosyltransferase 2B7 (UGT2B7)

Wogonin and its analogs for the prevention and treatment of cancer: A systematic review

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