Metabolic Profiling of Flavonol Metabolites in Human Urine by Liquid Chromatography and Tandem Mass Spectrometry

Hong, Yun-Jeong; Mitchell, Alyson E.

doi:10.1021/jf040274w

Cited by 69 publications

(54 citation statements)

References 42 publications

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“…Figure 5 shows that the 2 models adequately predicted urinary profiles with 1 to 4-fold and 1 to 7-fold accuracy 4 h and 24 3 h after consumption of onions corresponding to dose levels of 0.46 mg/kg bw Q4´Gly and 0.49 4 mg/kg bw Q34´diGly [23] and 0.95 Q4´Gly and 0.96 mg/kg bw Q34´diGly [10]. After 72 h 5 following consumption of 1.4 mg/kg bw 14 C-quercetin, 3.5 to 5.7% of the dose was recovered in 6 the urine which is 1 to 2-fold lower than the model prediction of 7.5% of the dose at the same 7 dose [24].…”

Section: Development Of the (Individual) Human Pbk Models And Evaluatmentioning

confidence: 96%

“…Mass balance equations for quercetin and its metabolites in tissues and blood were 8 similar to those previously described in the PBK model for quercetin in male rats [12]. Model 9 performance was assessed by comparing the predicted excretions via urine, bile and intestinal 10 enterocyte efflux back to lumen against available in vivo data [10,23,24]. With the obtained 11 model, the systemic bioavailability of quercetin aglycone and the nature and regiospecificity of 12 the major circulating quercetin metabolites in plasma were predicted.…”

Section: Definition Of the Pbk Model For (Individual) Human Subjects 21mentioning

confidence: 99%

“…With the adequate predictions of the plasma levels of the different metabolites obtainedcomparing the predicted excretion of quercetin metabolites via urine, bile and intestinal 1 enterocyte efflux back to lumen to the reported levels in vivo [10,23,24]. Figure 5 shows that the 2 models adequately predicted urinary profiles with 1 to 4-fold and 1 to 7-fold accuracy 4 h and 24 3 h after consumption of onions corresponding to dose levels of 0.46 mg/kg bw Q4´Gly and 0.49 4 mg/kg bw Q34´diGly [23] and 0.95 Q4´Gly and 0.96 mg/kg bw Q34´diGly [10].…”

Section: Development Of the (Individual) Human Pbk Models And Evaluatmentioning

confidence: 99%

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Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites

Boonpawa

Moradi

Spenkelink

et al. 2015

Biochemical Pharmacology

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This version is distributed under a non-commencial no derivatives Creative Commons (CC-BY-NC-ND) user license, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and not used for commercial purposes. Further, the restriction applies that if you remix, transform, or build upon the material, you may not distribute the modified material.Please cite this publication as follows: Biological activities of flavonoids in vivo ultimately depend on the systemic 3 bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based 4 kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its 5 metabolites in individual human subjects and to define species differences compared with male 6 rat. The human models were developed based on in vitro metabolic parameters derived from 7 incubations with pooled and 20 individual human tissue fractions and by fitting kinetic 8 parameters to available in vivo data. The outcomes obtained were compared to a previously 9 developed model for quercetin and its metabolites formation in male rat. Quercetin-3´-O-10 glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, 11 while in male rat di-and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or 12 methyl moiety are the major metabolites. Significant species differences occur in major 13 circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects 14 of quercetin in man. The defined PBK models can be used to guide the experimental design of in 15 vitro experiments with flavonoids, especially to better take into account the relevance of 16 metabolism and the contribution of metabolites to the biological activity in humans.

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Section: Development Of the (Individual) Human Pbk Models And Evaluatmentioning

confidence: 96%

Section: Definition Of the Pbk Model For (Individual) Human Subjects 21mentioning

confidence: 99%

Section: Development Of the (Individual) Human Pbk Models And Evaluatmentioning

confidence: 99%

See 1 more Smart Citation

Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites

Boonpawa

Moradi

Spenkelink

et al. 2015

Biochemical Pharmacology

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“…Multiple diglucuronides of quercetin and methyl quercetin have been reported in rat tissues after administration of 14 Clabeled quercetin glucoside (Graf et al, 2005). It is interesting to note that another study showed the presence of such multiple diglucuronides of quercetin in human urine after consumption of cooked onions (Hong and Mitchell, 2004). However, neither of these studies was able to point out the exact attachment of the glucuronic acid moieties on the molecules due to 1) the presence of multiple hydroxy groups on flavonoid molecules and 2) the fact that only tandem mass spectrometry data, but no NMR after isolation and collection of metabolite peaks, were reported.…”

Section: Diglucuronide Conjugatesmentioning

confidence: 96%

Unusual Glucuronides

Argikar¹

2012

Drug Metab Dispos

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ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

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“…Quercetin and its glycosides are the major phytochemicals of cranberry juice concentrate, and their metabolism and bioavailability are complex. Emerging evidence has indicated that these flavonoids are metabolized by UDP-glucuronyl transferase, sulfotransferases and methyl transferase forming several glucuronidated, sulfated and methylated conjugates, respectively, prior to reaching the systemic circulation (29)(30)(31)(32). We, therefore, analyzed aglycone quercetin and its methyl derivative in the urine and serum samples after enzymatic hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

Effect of cranberry juice concentrate on chemically-induced urinary bladder cancers

Prasain

Jones²,

Moore³

et al. 2008

Oncol Rep

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Abstract. The chemopreventive efficacy of cranberry juice concentrate in an experimental model of urinary bladder cancer was evaluated using female Fischer-344 rats. The animals received N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) for a period of eight weeks. Cranberry juice concentrate was administered at doses of 1.0 or 0.5 ml/rat/ day beginning one week after the final OH-BBN treatment and continuing until the end of the study. The urinary bladders of all the rats were weighed and examined grossly for lesions, and all masses were submitted for pathological evaluation. A dose-dependent preventive effect of cranberry treatment was observed, with a reduced number of urinary bladder cancers (38%) in the 1.0 ml/rat/day group versus the control group. The cranberry extract neither affected body weight gain nor caused other signs of toxicity. For the metabolic studies, serum and urine were collected at 4 and 12 h after the administration of the cranberry juice concentrate and were analyzed by LC-MS/MS. Quercetin and its methylated derivative were detected in the urine samples. However, no quercetin was detected in the serum samples, indicating its poor bioavailability. These data suggest that components of cranberries may be effective in preventing urinary bladder carcinogenesis. IntroductionNumerous epidemiological data have supported the inverse relationship between the consumption of fruit and vegetables and the incidence of urinary bladder cancer (1,2). The preventive effects of green tea leaves and one of its major components, epigallocatechin gallate (EGCG), have been reported for bladder cancer (3,4). The role of diet as a cause of urinary bladder carcinogenesis is feasible since most substances and/or their metabolites (including carcinogens) are excreted through the urinary tract. Importantly, the urinary concentration of these substances is substantially higher than in other tissues, thereby, enhancing their harmful activity. Foods that also contain significant amounts of cancer-preventive components may provide desirable health benefits beyond a basic nutritional function.The American cranberry (Vaccinium macrocarpon) contains the highest percentage of polyphenols by weight among 20 fruits analyzed in a previous study (5). Cranberry juice is well known for its possible beneficial effects in urinary tract infections (UTI), and considerable attention has been given to its active components and mechanism of action in vivo (6). Quercetin (Fig. 1), one of the major phytochemicals of the cranberry, has been reported to be a growth inhibitor of primary bladder transitional cell cancers in humans (7). Cancers of the urinary bladder were not observed in rats given a 5% quercetin diet (8). Synergistic or additive antiproliferative interactions of phytochemicals in a cranberry extract have recently been reported in several human tumor cell lines (9).Cranberry juice may be active in the prevention of UTI by blocking cell proliferation. Non-steroidal anti-inflammatory drugs (NSAIDs), which have antiproliferative a...

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Metabolic Profiling of Flavonol Metabolites in Human Urine by Liquid Chromatography and Tandem Mass Spectrometry

Cited by 69 publications

References 42 publications

Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites

Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites

Unusual Glucuronides

Effect of cranberry juice concentrate on chemically-induced urinary bladder cancers

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