Identification of Glutathione-Related Quercetin Metabolites in Humans

Hong, Yun-Jeong; Mitchell, Alyson E.

doi:10.1021/tx0601758

Cited by 27 publications

(29 citation statements)

References 61 publications

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“…Glucuronidation and sulfation are important metabolic routes for most flavonoids, while methylation or hydroxylation may also occur depending on the structure of the molecule in question [2,3]. There has also been a report of glutathionerelated metabolites in human urine [4]. As a result of these rapid conjugation reactions, neither the original flavonoid glycosides (except anthocyanins) nor the aglycon forms (except catechins) are found in plasma [5][6][7][8].…”

mentioning

confidence: 99%

Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

Davis

Brodbelt

2008

J. Am. Soc. Mass Spectrom.

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A three-part tandem mass spectrometric strategy that entails MS n analysis and a post-column LC-MS cobalt complexation method is developed to identify flavonoid monoglucuronide metabolites synthesized using the 1A1 isozyme of human UDP-glucuronosyltransferase (UGT). Ten flavonoid aglycons were used as substrates, spanning the subclasses of flavones, flavonols, and flavanones. The products were characterized by LC-MS and LC-MS n , with post-column cobalt complexation employed to pinpoint the specific sites of conjugation. The dissociation of complexes of the form [Co(II) (flavonoid glucuronide Ϫ H) (4,7-diphenyl-1,10-phenanthroline) 2 ] ϩ allowed identification of the products and differentiation of isomers. The correlation between glycosylation site and elution order is used to provide additional structural confirmation. Flavonoids lacking a 3= hydroxyl group were glucuronidated only at position 7, while those containing this functionality also formed 3=-O-glucuronides and sometimes 4=-O-glucuronides, thus supporting the conclusion that the presence or absence of the 3=-OH group is the major determinant of the regioselectivity of glucuronidation. Moreover, the specific distribution of multiple glucuronide products ( The currently accepted paradigm involves the consumption of flavonoid glycosides in plant-based food products, deglucosylation in the small intestine by ␤-glucosidase or lactose phloridzin hydrolase, and rapid metabolism by Phase I and (especially) Phase II enzymes [1][2][3]. Glucuronidation and sulfation are important metabolic routes for most flavonoids, while methylation or hydroxylation may also occur depending on the structure of the molecule in question [2,3]. There has also been a report of glutathionerelated metabolites in human urine [4]. As a result of these rapid conjugation reactions, neither the original flavonoid glycosides (except anthocyanins) nor the aglycon forms (except catechins) are found in plasma [5][6][7][8]. Early reports of unmodified flavonoid glycosides circulating in the bloodstream [9 -11] were likely mistaken identifications of flavonoid glucuronides, which have similar chromatographic and ultraviolet (UV) spectroscopic characteristics [7,12]. Flavonoids that fail to be absorbed in the small intestine may be broken down by microflora in the large intestine [1][2][3]. This process may release the free aglycons, which can then be absorbed and metabolized, but mostly results in the release of small phenolic acids, which are expelled in the urine [1][2][3]. Quantitative in vivo studies generally show that only a small percentage of consumed flavonoid glycosides is recovered in urine as conjugated Phase II metabolites [13][14][15]. Walle et al. used 14 Clabeled quercetin to show that up to 81% of the administered dose ultimately is exhaled in the form of carbon dioxide [16]. There remains considerable interest in the conjugated metabolites as they may retain some of the bioactivity of the original molecules [5,17].In spite of breakthroughs in the field of flavonoid metabol...

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confidence: 99%

Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

Davis

Brodbelt

2008

J. Am. Soc. Mass Spectrom.

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“…The proposed metabolites are shown in figure 4. Most of these metabolites have been described before (van der Woude et al , 2004, Hong andMitchell, 2006) although this the first study where they have been characterised by using high resolution mass spectrometry. In addition to quercetin metabolites, a small amount of the sulphate of D3 was formed.…”

Section: Lc-ms Analysismentioning

confidence: 99%

“…Quercetin was incubated with murine hepatocytes (Hong and Mitchell, 2006) and eighteen metabolites of quercetin were identified in the incubations including methylated, glucuronidated and sulphated metabolites but in addition a range of glutathione adducts were observed. These included the glutathione adducts of methyl quercetin and quercetin quinone and glucuronides of glutathione quercetin and methylquercetin.…”

Section: Introductionmentioning

confidence: 99%

The complex degradation and metabolism of quercetin in rat hepatocyte incubations

et al. 2014

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Abstract1. The current study demonstrated that there is still new information to be obtained on the chemical and biological transformation of the widely studied flavonoid quercetin.2. In rat hepatocytes thirty five metabolites of quercetin were observed by using high resolution mass spectrometry. The metabolites included glucuronides, sulphates, mixed sulphate/glucuronide metabolites and methylated versions of these metabolites.3. Several metabolites were formed from chemical degradation products of quercetin which were found to form in Krebs-Henseleit (KH) buffer, degradants of quercetin were also formed in the buffer under the conditions used for hepatocyte incubations.4. The degradants and metabolites of quercetin were characterised by using high resolution MS 2 . It was observed that the glutathione (GSH) conjugates of quercetin formed in large amounts in ammonium bicarbonate solution although the pattern of conjugates formed was different from that observed in hepatocytes suggesting some degree on enzymatic control on GSH conjugate formation in the hepatocyte incubations.5. GSH conjugates were not formed when GSH was included in incubations of quercetin in KH buffer alone and only small amounts of quercetin degradation occurred. Instead GSH was extensively converted into GSSG thus presumably reducing the levels of oxygen in the incubation thus preventing quercetin degradation.

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“…In cases where epoxides are generated because of vicinal hydroxyl groups on the polyphenol, the polyphenol can form glutathione conjugates (Fig. 7C) and eventually mercapturic acids 35 .…”

Section: Introductionmentioning

confidence: 99%

The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems

Barnes¹,

Prasain²,

et al. 2011

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Polyphenols in dietary and botanical matrices are usually present as simple and complex O-glycosides. In fermented dietary materials, the glycosidic moiety is removed and accompanied in some cases by more complex changes to the polyphenol. As for most xenobiotics, polyphenols undergo phase II conjugation in the intestinal wall during their absorption from the gut. In contrast, a few polyphenols, such as puerarin in the kudzu vine, are C-glycosides and are stable in the gut and during absorption, distribution and excretion. Large bowel bacteria reduce polyphenol aglycones, causing opening of the heterocyclic B-ring and ring cleavage. The products are mostly absorbed and enter the bloodstream. Phase I and II metabolism events occur in the intestine and the liver – most polyphenols predominantly circulate as β-glucuronides and sulfate esters with very little as the aglycones, the presumed active forms. In addition, metabolism can occur in non-hepatic tissues and cells including breast tumor cells that have variable amounts of cytochrome P450s, sulfatase and sulfotransferase activities. Inflammatory cells produce chemical oxidants (HOCl, HOBr, ONO2−) that will react with polyphenols. The isoflavones daidzein and genistein and the flavonol quercetin form mono- and dichlorinated products in reaction with HOCl. Genistein is converted to 3′-nitrogenistein in the lung tissue of lipopolysaccharide-treated rats. Whereas polyphenols that can be converted to quinones or epoxides react with glutathione (GSH) to form adducts, chlorinated isoflavones do not react with GSH; instead, they are converted to β-glucuronides and are excreted in bile. Analysis of polyphenols and their metabolites is routinely carried out with great sensitivity, specificity and quantification by LC-tandem mass spectrometry. Critical questions about the absorption and tissue uptake of complex polyphenols such as the proanthocyanins can be answered by labeling these polyphenols with 14C-sucrose in plant cell culture and then purifying them for use in animal experiments. The 14C signature is quantified using accelerator mass spectrometry, a technique capable of detecting one 14C atom in 1015 carbon atoms. This permits the study of the penetration of the polyphenols into the interstitial fluid, the fluid that is actually in contact with non-vascular cells.

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Identification of Glutathione-Related Quercetin Metabolites in Humans

Cited by 27 publications

References 61 publications

Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

Regioselectivity of human UDP-glucuronosyl-transferase 1A1 in the synthesis of flavonoid glucuronides determined by metal complexation and tandem mass spectrometry

The complex degradation and metabolism of quercetin in rat hepatocyte incubations

The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems

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