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C Rice-Evans

Publications and source records attributed to C Rice-Evans.

At least 19 recordsLinked to original sources
PubMed2001

Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts.

The purpose of this study was to examine the comparative mechanisms by which the dietary form of the flavonoid epicatechin and its predominant in vivo metabolite, epicatechin glucuronide, influence oxidative stress-induced cell death in fibroblasts and neurons. The results demonstrate the contrasting influences of in vivo glucuronidation and methylation on the bioactivity of epicatechin.

Animals↗
PubMed2001

Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3.

Oxidative stress has been associated with neuronal loss in neurodegenerative diseases and during age-associated cognitive decline. Flavonoids have been proposed to play a useful role in protecting the central nervous system against oxidative and excitotoxic stress, although the mechanism of action is unknown. Using oxidized low-density lipoprotein (oxLDL) as the oxidative insult we investigated the mechanism of neurotoxicity and attempted to identify possible sites of action of two of the most potent protective flavonoids, epicatechin and kaempferol, in cultured primary neurons. Using cultured striatal neurons and selective phosphospecific antibodies we addressed the potential role of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). OxLDL stimulated a Ca(2+)-dependent activation of both ERK1/2 and JNK that was strongly inhibited by pre-treatment with low micromolar concentrations of epicatechin. Neurotoxicity induced by oxLDL, however, was neither reduced nor enhanced by inhibiting ERK1/2 activation with mitogen-activated protein kinase kinase (MEK) inhibitors, suggesting that this cascade is unlikely to be involved in either oxLDL toxicity or the protective effects of flavonoids. oxLDL caused a sustained activation of JNK that resulted in the phosphorylation of the transcription factor c-Jun, which was abolished in neurons pre-treated with flavonoids. Furthermore, oxLDL induced the cleavage of procaspase-3 and increased caspase-3-like protease activity in neurons, an effect which was strongly inhibited by pre-exposure to either epicatechin or kaempferol. In addition, a caspase-3 inhibitor reduced oxLDL-induced neuronal death, implicating an apoptotic mechanism. A major in vivo metabolite of epicatechin, 3'-O-methyl-epicatechin was as effective as epicatechin in protecting neurons. Thus dietary flavonoids might have potential as protective agents against neuronal apoptosis through selective actions within stress-activated cellular responses, including protein kinase signalling cascades.

Animals↗
PubMed2001

Epicatechin is the primary bioavailable form of the procyanidin dimers B2 and B5 after transfer across the small intestine.

Perfusion of isolated small intestine with the procyanidin dimers B2 and B5 extracted from cocoa indicated that both forms of dimer are transferred to the serosal side of enterocytes but only to a very small extent (<1% of the total transferred flavanol-like compounds). However, perfusion of dimer mainly resulted in large amounts of unmetabolised/unconjugated epicatechin monomer being detected on the serosal side (95.8%). The cleavage of dimer during transfer seemed to be energy-dependent, requiring an intact cell system, as incubation with jejunal homogenates failed to yield epicatechin. Low levels methylated dimer were also detected (3.2%), but no conjugates and metabolites of epicatechin indicating that metabolism of monomer and dimer is limited during dimer cleavage/translocation. The methylation of dimer may be by catechol-O-methyltransferase, however, at high concentrations of dimer COMT activity is reduced leading to an inhibition of both monomer and dimer O-methylation.

Animals↗
PubMed2001

Epicatechin and its in vivo metabolite, 3'-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation.

There is considerable current interest in the cytoprotective effects of natural antioxidants against oxidative stress. In particular, epicatechin, a major member of the flavanol family of polyphenols with powerful antioxidant properties in vitro, has been investigated to determine its ability to attenuate oxidative-stress-induced cell damage and to understand the mechanism of its protective action. We have induced oxidative stress in cultured human fibroblasts using hydrogen peroxide and examined the cellular responses in the form of mitochondrial function, cell-membrane damage, annexin-V binding and caspase-3 activation. Since one of the major metabolites of epicatechin in vivo is 3'-O-methyl epicatechin, we have compared its protective effects with that of epicatechin. The results provide the first evidence that 3'-O-methyl epicatechin inhibits cell death induced by hydrogen peroxide and that the mechanism involves suppression of caspase-3 activity as a marker for apoptosis. Furthermore, the protection elicited by 3'-O-methyl epicatechin is not significantly different from that of epicatechin, suggesting that hydrogen-donating antioxidant activity is not the primary mechanism of protection.

Antioxidants↗
PubMed2001

Isomerization of lycopene in the gastric milieu.

There is considerable interest in the bioavailability of carotenoids from the diet and their bioactivity in vivo. Little is known, however, of the preabsorption events in the gastric lumen on the breakdown or isomerisation of dietary carotenoids. In this study the effects of the acidic environment found in the gastric milieu on lycopene have been investigated. The results show that under these conditions all-trans-lycopene is isomerised to cis-isomers, which may be implicated in enhanced absorption from the small intestine. Furthermore the pH, as well as the food matrix, seems to have an influence on the level of isomerisation of this carotenoid.

Beverages↗
PubMed2001

The mechanisms for nitration and nitrotyrosine formation in vitro and in vivo: impact of diet.

The detection of 3-nitro-L-tyrosine residues associated with many disease states, including gastric cancer, has implicated a role for peroxynitrite in vivo, and thus endogenously produced nitric oxide and superoxide. Additionally, dietary nitrate has been suggested to be involved in the pathogenesis of gastric cancer through a mechanism involving reduction to nitrite and subsequent formation of potentially mutagenic nitroso-compounds. Studies have now demonstrated that a multitude of reactive nitrogen species other than peroxynitrite are capable of producing nitrotyrosine. Thus, we have reviewed the evidence that dietary nitrate, amongst other reactive nitrogen species, may contribute to the body burden of nitrotyrosine.

Animals↗
PubMed2001

Lack of influence of dietary nitrate/nitrite on plasma nitrotyrosine levels measured using a competitive inhibition of binding ELISA assay.

The action of peroxynitrite in vivo has been proposed to account for the involvement of nitrotyrosine in the pathogenesis of many diseases. However, it has been demonstrated that nitrite under acidic conditions, similar to those in the human stomach, also has the ability to nitrate tyrosine. Dietary nitrate is also implicated in the progression of gastritis and gastric cancer and elevated levels of nitrate are found in many disease states in which nitrotyrosine may play a role. Thus, we investigated whether the dietary nitrate intake might contribute towards the plasma protein-bound levels of nitrotyrosine. Seven healthy, non-smokers participated in a two-day study consisting of a nitrate-low control day followed by a day during which three nitrate-rich meals were consumed. Maximal urinary excretion was attained 4-6 hours after consumption of a meal and the maximum was proportional to the dose. Plasma nitrate was elevated nine-fold, 1 hour after consumption of a meal containing 128.3 mg nitrate. Plasma nitrated protein levels did not appear to alter significantly from basal 1 hour after supplementation with a nitrate-rich meal. Thus dietary nitrate does not appear to contribute to the levels of plasma nitrated proteins, as determined using a competitive inhibition of binding ELISA assay, but this does not preclude any contribution it may make to the total body burden of nitrotyrosine.

Adult↗
PubMed2001

Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo.

There is considerable interest in the bioavailability of flavan-3-ols such as tea catechins and cocoa-derived procyanidin components of the diet and their bioactivity in vivo. Their hydrogen-donating abilities and their propensity for nitration make these compounds powerful scavengers of reactive oxygen and nitrogen species. In addition, recent evidence has suggested that these compounds may interact with redox-sensitive cell signaling pathways. However, their bioactivity in vivo will be dependent on the absorption and metabolism of these compounds after ingestion and the reducing properties of resulting metabolites. Many cell, animal, and human studies have shown that flavanol monomers, such as epicatechin, are extensively metabolised to O-methylated forms and/or conjugated to glucuronides and sulphates during absorption into the circulation. The cleavage of higher procyanidin oligomers to mixtures of monomer and dimer in the stomach may act to enhance the potential for their absorption in the small intestine as higher oligomers have very limited absorption. Studies suggest that the major bioactive forms of flavanol monomers and procyanidins in vivo are likely to be metabolites and/or conjugates of epicatechin. One such metabolite, 3'-O-methylepicatechin, has been shown to exert protective effects against oxidative stress-induced cell death. Future studies will continue to concentrate on the exact mechanism of action of the bioactive forms of flavan-3-ols in vivo.

Animals↗
PubMed2001

Flavonoid antioxidants.

In order to ascertain the role of dietary flavonoids as antioxidants in vivo it is necessary to understand the chemical nature of the absorbed forms in the circulation in vivo and how the multiplicity of research findings in vitro reflect the bioactivity of flavonoids in vivo. Only when we gain adequate information on the circulating forms can we begin to understand the targeting to the tissues, whether flavonoids cross the blood-brain barrier, for example, and in what forms. Flavonoids are powerful antioxidants in vitro, but their overall function in vivo has yet to be clarified, whether antioxidant, anti-inflammatory, enzyme inhibitor, enzyme inducer, inhibitor of cell division, or some other role. It should also be emphasised that the reducing properties of flavonoids might contribute to redox regulation in cells, independently of their antioxidant properties, and thus might protect against cell ageing, for example, by working together with the intracellular reductant network. To gain understanding of these issues the factors influencing the absorption of flavonoids in the gastrointestinal tract needs to be established, namely the questions of: de-glycosylation before absorption, conjugation in the small intestine through glucuronidation, sulphation or methylation etc, metabolism and degradation in the colon to smaller phenolic molecules. The forms in which they circulate in vivo will influence their polarity and, thus, their localization and bioactivities in vivo. Finally if antioxidant activities are important, the elucidation of how such properties in vitro relate to the potential for conjugates and metabolites in vivo to act as antioxidants is required. The absorbed flavonoid components might function in the aqueous phase (like vitamin C) or in the lipophilic milieu (as vitamin E) in vivo. This will depend on their polarity properties on uptake, how they are metabolised on absorption, and their resulting structural forms in the circulation.

Antioxidants↗
PubMed2000

Epicatechin and catechin are O-methylated and glucuronidated in the small intestine.

There is considerable interest in the bioavailability of polyphenols and their bioactivity in vivo. We have studied the absorption and metabolism of catechin and epicatechin in the small intestine and the comparative transfer across the jejunum and ileum. Perfusion of isolated jejunum with the flavanols resulted in glucuronidation ( approximately 45%), O-methylation: 3'-O-Methyl- and 4'-O-methyl- ( approximately 30%), and O-methyl-glucuronidation ( approximately 20% of total flavanols identified) during transfer across the enterocytes to the serosal side. This demonstrates the activity of catechol-O-methyl transferases in the metabolism of flavanols and suggests that these metabolites and conjugates are likely to enter the portal vein. In contrast, in the case of the ileum, the majority of the flavanols appeared on the serosal side unmetabolised and the total percentage of flavanols transferred was higher than that in the jejunum ( approximately fivefold).

Animals↗
PubMed2000

Decomposition of cocoa procyanidins in the gastric milieu.

There is considerable interest in the bioavailability of flavonoids and phenolic components of the diet and their bioactivity in vivo. However, little is known of pre-absorption events in the gastric lumen. The effects of the acidic environment, as found in the gastric milieu, on procyanidin oligomers of catechin polyphenols has been investigated. The results show that under these conditions the procyanidin oligomers (trimer to hexamer) are hydrolysed to mixtures of epicatechin monomer and dimer, thus enhancing the potential for their absorption in the small intestine.

Biflavonoids↗
PubMed2000

Resveratrol is absorbed in the small intestine as resveratrol glucuronide.

We have studied the absorption and metabolism of resveratrol in the jejunum in an isolated rat small intestine model. Only small amounts of resveratrol were absorbed across the enterocytes of the jejunum and ileum unmetabolised. The major compound detected on the serosal side was the glucuronide conjugate of resveratrol (96.5% +/- 4.6 of the amount absorbed) indicating the susceptibility of resveratrol to glucuronidation during transfer across the rat jejunum. The presence of the glucuronide was confirmed using HPLC-PDA and nanoES-MS/MS techniques. These findings suggest that resveratrol is most likely to be in the form of a glucuronide conjugate after crossing the small intestine and entering the blood circulation. This will have important implications for the biological functions of resveratrol in vivo.

Animals↗
PubMed2000

Ferulic acid excretion as a marker of consumption of a French maritime pine (Pinus maritima) bark extract.

French maritime pine (Pinus maritima) bark extract (PBE) is a polyphenol-rich food supplement patented under the name of Pycnogenol and known to have strong antioxidant activity and different beneficial effects on human health. Although its biological properties have begun to be extensively studied both in vitro, in laboratory animals and more recently in humans, little is known about its bioavailability. The present study investigated the urinary excretion of free and conjugated ferulic acid, present in quantitatively detectable amounts in PBE, after oral PBE administration to human subjects. Eleven healthy adult subjects (4 women and 7men) consumed either a single dose (200 mg PBE) or two doses of PBE (100 and 200 mg, respectively) within a 48-h interval. Two days before the oral administration of PBE and during the urine sample collection period volunteers adhered to a diet low in polyphenols. Aliquots of all urine production were collected over 24 h. Free and conjugated ferulic acid was assessed in urine by HPLC using diode array detection. A close association between the dietary intake of PBE and the urinary excretion of ferulic acid was detected. Moreover, the results indicate that a considerable proportion of ferulic acid is excreted as glucuronide or sulfate after PBE consumption, varying over the range 2 to 20% between individuals. The kinetics of excretion associated with the administration of 100 mg PBE was quite similar to that obtained after 200 mg PBE. A a biphasic trend was evident in a number of subjects. All subjects studied here displayed a significant, although variable level of excretion of ferulic acid after supplementation with PBE, Thus, the data provide evidence that at least a part of the phenolic components of PBE are absorbed, metabolized, and eliminated by humans.

Administration, Oral↗
PubMed2000

Absorption of ferulic acid from low-alcohol beer.

Flavonoids and monophenolic compounds have been well-described over recent years for their properties as antioxidants and scavengers of reactive oxygen and nitrogen species. A number of epidemiological studies implicate a role for flavonoids in reducing the risk of coronary heart disease. In particular, the focus has been on flavonol-rich fruit and vegetables and flavonoid-rich beverages, especially tea and red wine. Mechanisms of protection are unclear since the absorption, distribution, metabolism and elimination of dietary phenolics have not yet been extensively investigated. Here we report the bioavailability of ferulic acid, 4-hydroxy-3-methoxy-cinnamic acid, the major hydroxycinnamate in beer. Studies of the pharmacokinetics of urinary excretion of ferulic acid from low alcohol beer consumption in humans have been undertaken. The results show that ferulic acid is absorbed with a peak time for maximal excretion of ca. 8 h and the mean cumulative amount excreted is 5.8 +/- 3.2 mg. These findings are consistent with the uptake of ferulic acid from dietary sources, such as tomatoes, and suggest that ferulic acid is more bioavailable than individual dietary flavonoids and phenolics so far studied.

Adult↗
PubMed2000

Bioavailability of flavonoids and potential bioactive forms in vivo.

Flavonoids are powerful antioxidants in vitro, but their overall functions in vivo have yet to be clarified, whether antioxidant, anti-inflammatory, enzyme inhibitor or inducer, or some other role. The reducing properties of flavonoids might also contribute to redox regulation in cells independently of their antioxidant properties. However, in order to understand their bioactivity in vivo, it is necessary to understand the factors influencing the absorption of flavonoids by the gastrointestinal tract, the nature of the conjugates and metabolites in the circulation and how this influences their antioxidant activities.

Animals↗
PubMed1999

Moderate supplementation with natural alpha-tocopherol decreases platelet aggregation and low-density lipoprotein oxidation.

Previous studies have shown that oral administration of 300 mg alpha-tocopherol/day to healthy volunteers decreases platelet function and enhances their sensitivity to the platelet inhibitor, prostaglandin E(1), when full dose-response curves to a range of agonist concentrations are made. In this study, the effects of oral doses of natural alpha-tocopherol (75, 200 and 400 IU/day) were studied in order to determine whether the same effects might be achieved with lower intakes of vitamin E and whether inhibition is related to the platelet levels of the antioxidant in platelet membranes. Twenty two subjects undertook the supplementation regime, divided into three units of 2 weeks, each cycling through each of the dosages. The results show that uptake of vitamin E by the platelets was optimal at 75 IU/day, correlating with the maximal influence on platelet aggregation and platelet responsiveness to inhibition by PGE1, increased supplemental levels exerting no greater effects.

Adenosine Triphosphate↗
PubMed1999

The small intestine can both absorb and glucuronidate luminal flavonoids.

We have studied the perfusion of the jejunum and ileum in an isolated rat intestine model with flavonoids and hydroxycinnamates and the influence of glycosylation on the subsequent metabolism. Flavone and flavonol glucosides and their corresponding aglycones are glucuronidated during transfer across the rat jejunum and ileum and this glucuronidation occurs without the need for gut microflora. Furthermore, this suggests the presence of glycosidases as well as UDP-glucuronyl transferase in the jejunum. In contrast, quercetin-3-glucoside and rutin are mainly absorbed unmetabolised. The results suggest that the more highly reducing phenolics are absorbed predominantly as glucuronides (96.5%+/-4.6) of the amount absorbed, whereas monophenolic hydroxycinnamates and monophenolic B-ring flavonoids are less predisposed to glucuronidation and higher levels of aglycone (88.1%+/-10.1) are detected on absorption through both the jejunum and ileum.

Animals↗