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Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity.

Jones DJ, Lamb JH, Verschoyle RD, Howells LM, Butterworth M, Lim CK, Ferry D, Farmer PB, Gescher AJ - Br. J. Cancer (2004)

Bottom Line: Quercetin was less effective, with a 50% decline.Quercetin 3- and 7-O-sulphate had no effect on PGE-2.The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biomarkers and Prevention Group, Department of Biochemistry, Biocentre, University of Leicester, Leicester LE1 7RH, UK. djlj1@le.ac.uk

ABSTRACT
Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3'-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3'-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4'-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.

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High-performance liquid chromatography chromatograms of extracts of bile (A and B), plasma (C and D) or urine (E and F) from control rats (B, D and F) or rats that had received quercetin either 12.5 (A) or 6.25 mg kg−1 (C) and 2.5 g kg−1 (E) via the i.v. (A and C) or oral (E) routes. Bile was collected prior to (control) and for 20 min after the administration of quercetin; plasma samples were collected 5 min after administration of quercetin; urine samples were pooled over 8 h. Control (untreated) animals received the vehicle only via the appropriate administration route. Symbols i and ii denote retention times of quercetin and isorhamnetin, respectively. AU=absorbance units. For details of sample preparation and chromatographic analysis see Materials and Methods. The chromatograms shown are representative of extracts obtained from three separate animals.
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fig2: High-performance liquid chromatography chromatograms of extracts of bile (A and B), plasma (C and D) or urine (E and F) from control rats (B, D and F) or rats that had received quercetin either 12.5 (A) or 6.25 mg kg−1 (C) and 2.5 g kg−1 (E) via the i.v. (A and C) or oral (E) routes. Bile was collected prior to (control) and for 20 min after the administration of quercetin; plasma samples were collected 5 min after administration of quercetin; urine samples were pooled over 8 h. Control (untreated) animals received the vehicle only via the appropriate administration route. Symbols i and ii denote retention times of quercetin and isorhamnetin, respectively. AU=absorbance units. For details of sample preparation and chromatographic analysis see Materials and Methods. The chromatograms shown are representative of extracts obtained from three separate animals.

Mentions: High-performance liquid chromatography analysis of plasma and urine samples from rats, which had received quercetin (6.25 mg kg−1) via the i.v. route, contained quercetin (retention time 17.5 min, peak i in Figure 2Figure 2


Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity.

Jones DJ, Lamb JH, Verschoyle RD, Howells LM, Butterworth M, Lim CK, Ferry D, Farmer PB, Gescher AJ - Br. J. Cancer (2004)

High-performance liquid chromatography chromatograms of extracts of bile (A and B), plasma (C and D) or urine (E and F) from control rats (B, D and F) or rats that had received quercetin either 12.5 (A) or 6.25 mg kg−1 (C) and 2.5 g kg−1 (E) via the i.v. (A and C) or oral (E) routes. Bile was collected prior to (control) and for 20 min after the administration of quercetin; plasma samples were collected 5 min after administration of quercetin; urine samples were pooled over 8 h. Control (untreated) animals received the vehicle only via the appropriate administration route. Symbols i and ii denote retention times of quercetin and isorhamnetin, respectively. AU=absorbance units. For details of sample preparation and chromatographic analysis see Materials and Methods. The chromatograms shown are representative of extracts obtained from three separate animals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747694&req=5

fig2: High-performance liquid chromatography chromatograms of extracts of bile (A and B), plasma (C and D) or urine (E and F) from control rats (B, D and F) or rats that had received quercetin either 12.5 (A) or 6.25 mg kg−1 (C) and 2.5 g kg−1 (E) via the i.v. (A and C) or oral (E) routes. Bile was collected prior to (control) and for 20 min after the administration of quercetin; plasma samples were collected 5 min after administration of quercetin; urine samples were pooled over 8 h. Control (untreated) animals received the vehicle only via the appropriate administration route. Symbols i and ii denote retention times of quercetin and isorhamnetin, respectively. AU=absorbance units. For details of sample preparation and chromatographic analysis see Materials and Methods. The chromatograms shown are representative of extracts obtained from three separate animals.
Mentions: High-performance liquid chromatography analysis of plasma and urine samples from rats, which had received quercetin (6.25 mg kg−1) via the i.v. route, contained quercetin (retention time 17.5 min, peak i in Figure 2Figure 2

Bottom Line: Quercetin was less effective, with a 50% decline.Quercetin 3- and 7-O-sulphate had no effect on PGE-2.The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biomarkers and Prevention Group, Department of Biochemistry, Biocentre, University of Leicester, Leicester LE1 7RH, UK. djlj1@le.ac.uk

ABSTRACT
Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3'-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3'-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4'-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.

Show MeSH
Related in: MedlinePlus