Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases

Guo, Bin; Fang, Zhong‐Ze; Lü, Yang; Xiao, Ling; Xia, Yangliu; Gonzalez, Frank J.; Zhu, Liangliang; Cao, Yun‐Feng; Ge, Guangbo; Yang, Ling; Sun, Hongzhi

doi:10.1016/j.cbi.2015.03.001

Cited by 13 publications

(10 citation statements)

References 26 publications

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“…Unlike the cytochrome P450 enzymes, the UGT enzymes in mammals have significantly varying species differences in both expression and function, while the substrate and inhibitor spectra of the major UGT enzymes are much different from species to species (Higashi et al, 2014;Liang et al, 2011;Guo et al, 2015;Wen et al, 2007). In these cases, we predicted the potential risk of LCA-associated inhibition on human UGTs based on a series of available data (Table 4).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 μM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates.

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Section: Discussionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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“…GLA, a flavonoid extracts from the phytochemical licorice, has multiple biological activities [ 14 ], such as estrogen-like [ 26 ] and anti-inflammatory activities [ 27 ]. In addition, GLA can activate caspase-3, −8, and −9 to induce HL-60 cell apoptosis through the regulation of the p38 MAPK and JNK1/2 pathways [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Licorice root is a kind of traditional Chinese medicine that has been accepted for menopausal symptoms, coughing and fever [ 14 , 15 ]. Glabridin(GLA), an isoflavane compound in licorice roots, has attracted extensive attention because of its various biological properties, including the anti-proliferative [ 16 ], anti-stem cell-like [ 17 ], and anti-cancer activities [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

The repressive effect of miR-148a on Wnt/β-catenin signaling involved in Glabridin-induced anti-angiogenesis in human breast cancer cells

Zhu

Shen

et al. 2017

BMC Cancer

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BackgroundGlabridin (GLA), a major component extracted from licorice root, has anti-inflammatory and antioxidant activities, but few studies report its mechanism of inhibition of angiogenesis. This study was an extension of our previous work, which demonstrated that GLA suppressed angiogenesis in human breast cancer (MDA-MB-231 and Hs-578T) cells. Breast cancer is one of the most common malignant diseases in females worldwide, and the major cause of mortality is metastasis that is primarily attributed to angiogenesis. Thus, anti-angiogenesis has become a strategy for the treatment of breast cancer.MethodsCell viability of different concentration treatment groups were detected by Cell Counting Kit-8 assay. The expression of several related genes in the Wnt1 signaling pathway in MDA-MB-231 and Hs-578T cells treated with GLA were measured at both the transcription and translation levels using quantitative real-time PCR analyses and western blotting. Immunofluorescence assay analyzed the nuclear translocation of β-catenin. The microRNA-inhibitor was used to knockdown microRNA-148a (miR-148a) expression. Angiogenic potentials of breast cancer cells were analyzed by enzyme-linked immunosorbent assay (ELISA) and tube formation in vitro.ResultsGLA attenuated angiogenesis by the suppression of miR-148a-mediated Wnt/β-catenin signaling pathway in two human breast cancer cell lines (MDA-MB-231 and Hs-578T). GLA also upregulated the expression of miR-148a in a dose-dependent manner, miR-148a, which could directly target Wnt-3′-untranslated regions (UTRs), and decreased the expression of Wnt1, leading to β-catenin accumulation in the membranes from the cytoplasm and nucleus. Downregulation of miR-148a contributed to the reduction of GLA-induced suppression of the Wnt/β-catenin signaling pathway, the angiogenesis and vascular endothelial grow factor (VEGF) secretion.ConclusionsOur study identified a molecular mechanism of the GLA inhibition of angiogenesis through the Wnt/β-catenin signaling pathway via miR-148a, suggesting that GLA could serve as an adjuvant chemotherapeutic agent for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3298-1) contains supplementary material, which is available to authorized users.

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“…It is known to have whitening activity by suppressing the activity of tyrosinase during the synthesis of melanin and to help alleviate gastroenteric disorders. Recently, it was confirmed that glabridin is effective in metabolic syndromes, including hyperlipidemia, fatty liver, impaired glucose metabolism, diabetes, and obesity and has anti-inflammatory actions, anticancer actions, and the like [4]. However, in spite of useful medicinal efficacy, glabridin is easily broken down by sunlight, moisture, acidity, basicity, oxygen, heat, and the like due to low chemical stability, so it is very difficult to develop a product actually utilizing glabridin [4].…”

Section: Introductionmentioning

confidence: 99%

“…For these reasons, we synthesized a new pyranochromenylphenol derivative, HSG4112, by modifying the structure of glabridin. HSG4112 is stable under various physical conditions, while maintaining or improving its medicinal efficacy [4]. HSG4112 is a racemic compound with a chiral carbon.…”

Section: Introductionmentioning

confidence: 99%

Species Differences in Stereoselective Pharmacokinetics of HSG4112, A New Anti-Obesity Agent

Bae

Choi

et al. 2020

Pharmaceutics

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HSG4112, a racemic drug, is a new anti-obesity agent. In this study, the stereoselective pharmacokinetics of HSG4112 were investigated in rats and dogs, and the underlying mechanism was investigated. The plasma concentrations of HSG4112(S) and HSG4112(R) were quantitated in plasma from rats and beagle dogs after IV and/or oral administration of racemic HSG4112. The concentration of HSG4112(S) was significantly higher than that of HSG4112(R) in rat plasma. Contrarily, the concentration of HSG4112(R) was significantly higher than HSG4112(S) in dog plasma. A metabolic stability test with liver microsomes showed that HSG4112(S) was more stable than HSG4112(R) in rat liver microsomes, but the difference between stereoisomers did not appear in dog liver microsomes. However, the stereoselectivity was observed in dog liver and intestinal microsomes after uridine 5’-diphospho-glucuronic acid was added. Thus, stereoselective metabolism by uridine 5’-diphospho-glucuronosyltransferases is mainly responsible for the stereoselective pharmacokinetics in dogs. These results suggest that the species difference in the stereoselective plasma pharmacokinetics of HSG4112 is due to the stereoselective metabolism.

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Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases

Cited by 13 publications

References 26 publications

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

The repressive effect of miR-148a on Wnt/β-catenin signaling involved in Glabridin-induced anti-angiogenesis in human breast cancer cells

Species Differences in Stereoselective Pharmacokinetics of HSG4112, A New Anti-Obesity Agent

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