Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes

Dai, Peimin; Luo, Feifei; Wang, Ying; Jiang, Hongbin; Wang, Liping; Zhang, Guiyu; Zhu, Lijun; Hu, Ming; Wang, Xinchun; Lu, Linlin; Liu, Zhongqiu

doi:10.1002/bdd.1989

Cited by 26 publications

(15 citation statements)

References 38 publications

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“…The glucuronidation characteristics of the flavonoid glucoside tilianin and its aglycone acacetin (flavones) were characterized with the use of human UGT isoforms, liver microsomes, and intestinal microsomes that were obtained from different animal species. Overall, and consistent with Kawase et al (61), higher glucuronidation rates attributed to higher UGT1A1 activities were evident in females across several species (62). The impact of aging on the glucuronidation of quercetin and genistein in male rat hepatic microsomes was also studied (63).…”

Section: Etiology Of the Heterogeneity In Flavonoid Admesupporting

confidence: 88%

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

Cassidy

Minihane

2017

The American Journal of Clinical Nutrition

404

287

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At a population level, there is growing evidence of the beneficial effects of dietary flavonoids on health. However, there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes. In addition, food composition and flavonoid source are likely to affect bioavailability, and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main subclasses of flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones, for which there is growing evidence from prospective studies of beneficial effects on health. The identification of key factors that govern metabolism and an understanding of how the differential capacity to metabolize these bioactive compounds affect health outcomes will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas that need to be addressed to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base that is required to move toward the development of dietary guidelines and recommendations for flavonoids and flavonoid-rich foods.

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Section: Etiology Of the Heterogeneity In Flavonoid Admesupporting

confidence: 88%

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

Cassidy

Minihane

2017

The American Journal of Clinical Nutrition

404

287

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“…Furthermore, data from our lab also showed that higher resveratrol concentrations inhibit the formation of resveratrol-3-O-sulfate, which might also be observed in mice [ 24 ]. We decided to use male and not female mice in all experiments as recent papers [ 25 , 26 ] described significant gender-dependent differences in the glucuronidation of drugs and flavonoids in mice, with a higher formation rate of glucuonides in females than in males, which might be also true for resveratrol. In humans, such pronounced gender-difference in glucuronidation has not been observed so far.…”

Section: Discussionmentioning

confidence: 99%

Involvement of UDP-Glucuronosyltransferases and Sulfotransferases in the Excretion and Tissue Distribution of Resveratrol in Mice

et al. 2017

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Resveratrol is a naturally occurring polyphenolic compound with various pharmacological activities. It is unknown whether the expression of metabolizing enzymes correlates with resveratrol levels in organs and tissues. Therefore, we investigated the metabolism and tissue distribution of resveratrol in mice and assessed its association with the expression of UDP-glucuronosyltransferase (Ugt) and sulfotransferase (Sult) genes. Plasma, urine, feces, and various organs were analyzed using high-performance liquid chromatography at up to 8 h after intragastric resveratrol administration. The metabolism of resveratrol was pronounced, leading to the formation of resveratrol glucuronides and sulfates. Concentrations of resveratrol and its metabolites were high in the gastrointestinal organs, urine, and feces, but low in the liver and kidneys. In lung, heart, thymus, and brain tissues, parent resveratrol levels exceeded the sulfate and glucuronide concentrations. The formation of resveratrol conjugates correlated with the expression of certain Ugt and Sult genes. Reverse transcription quantitative PCR (RT-qPCR) analysis revealed high mRNA expression of Ugt1a1 and Ugt1a6a in the liver, duodenum, jejunum, ileum, and colon, leading to high concentrations of resveratrol-3-O-glucuronide in these organs. Strong correlations of resveratrol-3-O-sulfate and resveratrol-3-O-4′-O-disulfate formation with Sult1a1 mRNA expression were also observed, particularly in the liver and colon. In summary, our data revealed organ-specific expression of Sults and Ugts in mice that strongly affects resveratrol concentrations; this may also be predictive in humans following oral uptake of dietary resveratrol.

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“…In HLMs, the CL int value of diosmetin through 3′-OH was much higher than that of the 7-OH, and the CL int value of chrysoeriol through 4′-OH was about 32 times than that of the 7-OH pathway. For another, the K m values of diosmetin and chrysoeriol glucuronides were lower than a series of 7-OH, 3’-OH or 4’-OH flavonoids, such as acacetin glucuronide (K m was 14.465 μM)[34] and genistein glucuronides (K m was 15.1 μM)[35] (Table 1). …”

Section: Discussionmentioning

confidence: 99%

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

et al. 2016

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This study aimed to determine the reaction kinetics of the regioselective glucuronidation of diosmetin and chrysoeriol, two important methylated metabolites of luteolin, by human liver microsomes (HLMs) and uridine-5′-diphosphate glucuronosyltransferase (UGTs) enzymes. This study also investigated the effects of breast cancer resistance protein (BCRP) on the efflux of diosmetin and chrysoeriol glucuronides in HeLa cells overexpressing UGT1A9 (HeLa—UGT1A9). After incubation with HLMs in the presence of UDP-glucuronic acid, diosmetin and chrysoeriol gained two glucuronides each, and the OH—in each B ring of diosmetin and chrysoeriol was the preferable site for glucuronidation. Screening assays with 12 human expressed UGT enzymes and chemical-inhibition assays demonstrated that glucuronide formation was almost exclusively catalyzed by UGT1A1, UGT1A6, and UGT1A9. Importantly, in HeLa—UGT1A9, Ko143 significantly inhibited the efflux of diosmetin and chrysoeriol glucuronides and increased their intracellular levels in a dose-dependent manner. This observation suggested that BCRP-mediated excretion was the predominant pathway for diosmetin and chrysoeriol disposition. In conclusion, UGT1A1, UGT1A6, and UGT1A9 were the chief contributors to the regioselective glucuronidation of diosmetin and chrysoeriol in the liver. Moreover, cellular glucuronidation was significantly altered by inhibiting BCRP, revealing a notable interplay between glucuronidation and efflux transport. Diosmetin and chrysoeriol possibly have different effects on anti-cancer due to the difference of UGT isoforms in different cancer cells.

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Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes

Cited by 26 publications

References 38 publications

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

Involvement of UDP-Glucuronosyltransferases and Sulfotransferases in the Excretion and Tissue Distribution of Resveratrol in Mice

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

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