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

Abstract

Quercetin (3,5,7,3 0 ,4 0 -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 0 -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 0 -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 0 -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. Naturally occurring flavonoids in the diet are associated with several beneficial health effects and understanding the mechanisms underlying these effects has become the focus of much research. Quercetin (3,5,7,3 0 ,4 0 -pentahydroxyflavone, for structure see Figure 1) is a prime example of such a flavonoid. Its glycosylated form occurs in kale, French beans, broccoli, apples and especially in onions, with an abundance as high as a quarter to half a gram per kg (Hertog et al, 1992). On ingestion with the diet, quercetin glycosides are rapidly hydrolysed to generate quercetin.Epidemiological evidence links diets rich in quercetin with decreased incidence of cardiovascular and neoplastic diseases

Differential hepatoprotective mechanisms of rutin and quercetin in CCl4-intoxicated BALB/cN mice

“…The nuclear presence of COX-2 and iNOS suggests their involvement in the regulation of some nuclear functions. However, rutin exhibited lower potency in reducing COX-2 expression compared with quercetin, which is in agreement with previous findings [35] . Interestingly, rutin more effectively suppressed the expression of both iNOS and 3-NT compared with quercetin.…”

Isolation and Structure Identification of Flavonoids

“…Strong regularities are also shown in 13 C-NMR spectra of flavonoids. The types of flavonoids, number and connection positions of glycosyls could be elucidated from 13 C-NMR spectra.…”

“…The types of flavonoids, number and connection positions of glycosyls could be elucidated from 13 C-NMR spectra.…”

“…Furthermore, flavonoids possess various pharmacological activities of inhibiting the activity of enzymes, antitumor, antibiosis, antivirus, anti-inflammatory and so on [3][4][5][6][7][8][9]. The potential treatment and prevention effects have been shown in degenerative diseases such as tumors, aging and cardiovascular diseases [10][11][12][13][14][15]. Additionally, some compounds of flavonoids possess potential application prospects as weak hormones at treating menopausal syndrome of women [14][15][16][17].…”

Cyclooxygenase-2 and Inflammation Mediators Have a Crucial Role in Reflux-Related Esophageal Histological Changes and Barrett’s Esophagus

“…COX-1 is considered a housekeeping gene and is constitutively expressed in most normal tissues, whereas COX-2 is an inducible enzyme, which can be rapidly induced by cytokines, inflammatory mediators, growth factors and tumour promoters and is related to human inflammatory diseases and carcinogenesis in different tissues [1][2][3][4][5]. A large body of evidence suggests that induction of COX-2 plays a pivotal role in cancer development by promoting cell proliferation, decreasing apoptosis rate, stimulating angiogenesis and increasing invasive and metastatic potential of the primary tumour [6][7][8][9]. A role of COX-2 in carcinogenesis is also indirectly supported by a wealth of epidemiological data which have shown an association of the long-term use of non steroidal anti-inflammatory drugs (NSAIDs) with a decreased incidence of colorectal, gastric and oesophageal cancers [10].…”