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Antioxidants Research Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University and * The Almond Board of California, Modesto, CA
3To whom correspondence should be addressed. E-mail: jeffrey.blumberg{at}tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT METHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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0.0001). Combining ASF with vitamin E or ascorbic acid extended the lag time >200% of the expected additive value (P 0.05). The bioavailability and in vivo antioxidant activity of 40 µmol ASF were examined in BioF1B hamsters. Peak plasma concentrations of catechin, epicatechin, and flavonols (quercetin, kaempferol, and isorhamnetin) occurred at 60, 120, and 180 min, respectively. The concentration of isorhamnetin was significantly elevated in liver at 180 min. Absorbed ASF enhanced the ex vivo resistance of hamster LDL collected at 60 min to oxidation by 18.0% (P = 0.028), and the in vitro addition of 5.5 µmol/L vitamin E synergistically extended the lag time of the 60-min sample by 52.5% (P 0.05). Thus, ASF possess antioxidant capacity in vitro; they are bioavailable and act in synergy with vitamins C and E to protect LDL against oxidation in hamsters.
KEY WORDS: • almonds • antioxidants • bioavailability • flavonoids • synergy
Flavonoids are natural constituents of plant foods and have been carefully studied in fruits and vegetables, but less attention has been paid to their presence in whole grains and tree nuts (1,2). Flavonoids appear to possess a variety of biological activities, including antioxidant, anti-inflammatory, and vasodilatory actions (3). Putative health benefits of flavonoids were suggested by epidemiologic studies showing an inverse association between intake and risk of cardiovascular disease (4,5). A similar relation was observed with tree nuts, leading to the recent approval by the FDA of a qualified health claim for tree nuts, including almonds, that eating 42.6 g/d (1.5 oz/d) as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease (6). It is worth noting here the randomized clinical trial conducted by Jenkins et al. (7) demonstrating that almond consumption can reduce total and LDL cholesterol and increase the resistance of LDL to oxidation.
Almonds (Prunus amygdalus Batsch) rank highest among tree nuts, such as hazelnut, pecan, pistachio, and walnut, in total annual crop production (8), and are a good source of nutrients associated with heart health such as vitamin E, monounsaturated fatty acids, PUFA, arginine, and potassium (9). Almond skins, removed from the nut by hot water blanching during preparation of almond meat, constitute 
4% of the total almond weight and are generally treated as a waste product. However, an array of flavonoids, including catechins, flavonols, and flavanones in their aglycone and glycoside forms, were identified in almond skin (10,11). These compounds may contribute to the health benefits associated with almond consumption. The bioavailability and pharmacokinetics of individual flavonoids were demonstrated in several studies (12–14). Catechins and flavonols from food were also found to be bioavailable in rodent and human studies with the food, although its matrix and preparation may have a significant effect on their bioavailabilities (15–20). However, no studies have explored the bioavailability of flavonoids from almond skins and their effect on antioxidant activity. Therefore, we examined almond skin flavonoids (ASF)4 for their in vitro action with and without vitamins C and E on the resistance of human LDL to oxidation as well as their bioavailability, pharmacokinetics, and in vivo antioxidant actions in hamsters.
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METHODS AND MATERIALS |
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-tocopherol), sodium chloride, quercetin, catechin, (-)-epicatechin, kaempferol, isorhamnetin, sodium phosphate monobasic, sodium phosphate dibasic, BHT, Folin Ciocalteu phenol reagent, and ß-glucuronidase type H-2 (containing sulfatase from Helix pomatia). All organic solvents, glacial acetic acid, food-grade ascorbic acid, and potassium bromide were purchased from Fisher. Flavonoid profile of almond skin. Pulverized almond skin powder provided by the Almond Board of California was used for ASF extraction. The powder (0.5 g) was extracted twice with 10 mL acidified methanol solution (HCl:H2O:methanol, 1:19:80) over 16 h at 4°C. The sample was centrifuged at 1000 x g for 15 min at 4°C and methanol evaporated with nitrogen gas. The residue was reconstituted with the aqueous mobile phase and the ASF characterized by HPLC with electrochemical detection (ECD) according to a slightly modified method of Milbury (21). The residue was also reconstituted with phosphate buffer (7.79 mmol/L Na2HPO4, 2.59 mmol/L NaH2PO4, and 150 mmol/L NaCl, pH 7.4) for the in vitro LDL oxidation assay. All HPLC procedures were performed with ESA instruments, including 2 pumps (model 582), autosampler (model 542), and Coularray 5600 A detector. Analyte separation was achieved using a Zorbax ODS C18 column (4.6 x 150 mm, 3.5 µm) with a 0.6 mL/min flow rate and mobile phase gradient from mobile phase A (75 mmol/L citric acid and 25 mmol/L ammonium acetate in 90% H2O and 10% acetonitrile) to mobile phase B (75 mmol/L citric acid and 25 mmol/L ammonium acetate in 50% H2O and 50% acetonitrile) for 68 min. The following mobile phase gradient profile was used (% solvent B): 1% (0–15 min), 1–10% (15–25 min), 10–80% (25–60 min), 80–10% (60–65 min), and 10–1% (65–68 min). Detection was achieved with potentials applied from 60 to 720 mV with 60-mV increments. The identification of individual ASF was achieved by comparing its retention time and electrochemical response with purified standards obtained from Sigma Chemical. The quantity of individual almond flavonoids was calculated according to concentration curves constructed with purified standards. Total almond skin phenolics were assessed via the Folin-Ciocalteu reaction according to Singleton et al. (22) and expressed as µmol/L gallic acid equivalents (GAE).
Antioxidant capacity of ASF in human LDL.
The antioxidant capacity of ASF was assessed in vitro with human LDL according to a slight modification of the method described by Esterbauer et al. (23). Collection of venous blood, approved by the Institutional Review Board of the Tufts-New England Medical Center, was performed between 1400 and 1430 h in 6 healthy Caucasian women who were not fasting; the women were 28–64 y old with a mean body weight of 63 ± 15 kg. LDL was separated from plasma according to Chung et al. (24) using a Beckman NVT-90 rotor in a Beckman L8-mol/L centrifuge (329,271 x g for 90 min). KBr and EDTA were removed from the sample using a PD-10 column (Amersham Pharmacia Biotech). LDL protein was determined using a bicinchoninic acid protein assay kit (Pierce). LDL samples from the first 3 subjects were used to assess the dose-response relation of ASF, and from the last 3 subjects for experiments on the interaction between ASF with vitamins C and E. All LDL experiments were performed in duplicate in each of 3 subjects. LDL (182 nmol/L) were oxidized by 10 µmol/L CuSO4 in a total volume of 1.0 mL phosphate buffer (7.79 mmol/L Na2HPO4, 2.59 mmol/L NaH2PO4, and 150 mmol/L NaCl, pH 7.4). Formation of conjugated dienes was monitored by absorbance at 234 nm at 37°C over 6 h using a Shimadzu UV1601 spectrophotometer (Japan) equipped with a 6-position automated sample changer. The results of the LDL oxidation are expressed as lag time (defined as the intercept at the abscissa in the diene-time plot) (25). An aliquot of ASF in acidified methanol was dried under nitrogen and redissolved in an equal volume of phosphate buffer (pH 7.4) for testing in the assay. Concentrations ofASF from 0.18 to 1.44 µmol/L were selected to reflect amounts that can be obtained from dietary intakes (26). Concentrations of vitamin E and C employed in these experiments were 9–18% and 3–6% of plasma concentrations, respectively, levels generally found in healthy people (27). Vitamin E (-tocopherol) was dissolved in methanol and subsequently diluted with phosphate buffer to obtain the selected concentrations; the final concentration of methanol was 0.5%. ASF and vitamin E were incubated with LDL at 37°C for 30 min before initiation of oxidation, and ascorbic acid was dissolved in PBS and added to the reaction immediately before initiation of oxidation. The effect of ASF plus vitamin C or E on the resistance of LDL to oxidation was expressed as the lag time increase compared with the lag time of LDL without the addition of ASF or vitamin C or E.
Preparation of ASF for hamster gavage. ASF were extracted with acidic aqueous methanol as described above with the substitution of white vinegar for HCl. Methanol was removed using a Rotavapor 134 (Buchi, Brinkmann Instrument) and the resulting slurry used for the hamster gavage.
Animals. BioF1B strain Golden Syrian Hamsters (n = 22; BioBreeders) were used in the bioavailability experiments due to the similarity of their lipoprotein metabolism to that of humans (28). The 1-y-old hamsters, with a body weight of 136.0 ± 1.2 g (mean ± SE), were housed individually in cages with a 10:14 h light:dark cycle. To increase lipoprotein production for subsequent collection, hamsters consumed ad libitum a nonpurified diet (Harlan) enriched with 10 g coconut oil and 0.5 g cholesterol/100 g for 2 wk before the acute administration of the ASF slurry (29).
After overnight food deprivation, hamsters were randomly assigned on the basis of their body weight to 6 time point groups: 0 (baseline), 60, 90, 120, 180, and 300 min (n = 4, 4, 4, 4, 4, and 2, respectively). Because Kühnau (30) estimated daily intake of flavonoids and other polyphenolics by a person weighing 70 kg at 14 mg/kg, we chose a test dose of 50 mg/kg body weight or 40 µmol GAE/hamster because rodents consume 5–6 times more food-based energy per unit of body weight than humans (31). Thus, ASF with 40 µmol GAE (6.8 mg) was delivered in 1.0 mL via stomach gavage to hamsters anesthetized with AerraneTM (Baxter); 1.0 mL saline was administered to the baseline group. Blood from each hamster was collected from the orbital sinus via micro-hematocrit tubes coated with heparin and stored in microtubes containing ETDA. Plasma samples were collected after the whole blood was centrifuged at 1000 x g for 15 min at 4°C. An aliquot of plasma was stored at –80°C for determination of flavonoid status with the remainder used immediately for analysis of LDL oxidation. Whole liver was removed, rinsed with saline, and snap-frozen in liquid nitrogen for additional flavonoid analysis. This study was approved by the Animal Care and Use Committee of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.
Analysis of plasma and liver flavonoids. ASF in hamster plasma and liver were assessed by the HPLC-ECD as described above. Briefly, 20 µL vitamin C-EDTA (200 mg ascorbic acid plus 1 mg EDTA in 1.0 mL of 0.4 mol/L NaH2PO4, pH 3.6) and 20 µL ß-glucuronidase (98,000 kU/L ß-glucuronidase and 2400 kU/L sulfatase) were added to 200 µL plasma and the mixture was incubated at 37°C for 45 min. ASF were extracted with 500 µL acetonitrile; 500 µL of supernatant was removed following a vigorous vortex for 30 s and centrifugation at 14,000 x g for 5 min, dried under purified nitrogen, and reconstituted in 200 µL of the aqueous HPLC mobile phase. After centrifugation at 14,000 x g for 5 min, 100 µL of supernatant was injected into the HPLC.
Liver samples (0.5 g) frozen in liquid nitrogen were pulverized and extracted twice with 5 mL acetonitrile containing 0.01% BHT. The supernatant was removed after centrifugation at 14,000 x g for 5 min, combined, dried under nitrogen, and reconstituted in 500 µL of 1 mol/L sodium acetate buffer, pH 5.5. After incubation with 10 µL ß-glucuronidase (98,000 kU/L ß-glucuronidase and 2400 kU/L sulfatase) at 37°C overnight, the mixture was processed in the same manner as plasma samples. Due to a lower volume of ß-glucuronidase and different buffer system, deconjugation of flavonoid metabolites took longer in liver than in plasma samples. Spiked, purified stan-dards, rather than an internal standard, were added at the beginning of sample processing to construct standard curves and account for extraction losses and quantify concentrations (2). The recovery rates of spiked standards ranged from 75 to 80%.
Ex vivo antioxidant capacity of ASF. The ex vivo resistance of hamster LDL to Cu2+-induced oxidation was performed as described above for the in vitro experiments to test antioxidant activity of flavonoids in ASF-gavaged hamsters. Because hamster LDL obtained through ultracentrifugation was lower than human LDL (determined by protein content), 91 nmol/L LDL was oxidized by 5 µmol/L CuSO4 in a total volume of 1.0 mL phosphate buffer (pH 7.4). Based on the synergistic results obtained with ASF plus vitamin E in the in vitro experiments, vitamin E was added in vitro to hamster LDL to a final concentration of 5.5 µmol/L before initiation of oxidation.
Statistics.
All results are reported as means ± SE. The Tukey-Kramer honestly significant difference test was used in experiments on ASF in hamster plasma, and in vitro hamster and human LDL oxidation after significant differences were obtained by one-way ANOVA. The equal variance assumption was assessed by Hartley’s test (32) and data, including epicatechin and isorhamnetin in plasma and catechin, epicatechin, quercetin, and kaempferol in liver, were square root-transformed before ANOVA analysis (2). The difference in lag time of ex vivo hamster LDL oxidation between baseline and ASF administration was determined by a simple t test. A paired t test was performed to determine the significance of the synergy between ASF and vitamins C or E in the in vitro human LDL oxidation by comparing the observed lag time during co-incubation with the expected (calculated) sums of values observed for ASF and vitamin C or E treatment alone. Data from all time points was included in correlation tests. Differences with P 0.05 were considered significant. The JMP IN 4 statistical software package (SAS Institute) was used to perform all statistical analyses.
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RESULTS |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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30 peaks with detectable redox potential, indicating the presence of numerous potential antioxidant compounds in almond skin (Fig. 1). Five aglycone flavonoids were identified and quantified as follows (nmol/g): catechin (186.9), epicatechin (77.5), isorhamnetin (20.8), quercetin (6.0), and kaempferol (3.9). These 5 flavonoids represent 3.6% of the total phenolic content of almond skins.
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0.0001) (Fig. 2). Ascorbic acid at 2.5 and 5.0 µmol/L increased lag time by 12.9 ± 1.6 and 34 ± 2.7 min, respectively; vitamin E at 2.75 and 5.5 µmol/L increased lag time by 19.1 ± 1.4 and 24.3 ± 0.7 min, respectively. A 1-fold synergy (i.e., an observed value twice the calculated additive value) was observed with 0.18 and 0.36 µmol/L of ASF in combination with 5.0 µmol/L ascorbic acid (P 0.01); no synergy was observed with the 2.5 µmol/L dose of vitamin C (Fig. 3A). The lag time was 289% longer than the expected additive value with the combination of 0.36 µmol/L ASF and 5.5 µmol/L vitamin E (P 0.001) (Fig. 3B).
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0.05). Concentrations of quercetin and kaempferol were correlated (Table 1). Isorhamnetin pharmacokinetics paralleled those of kaempferol, but not quercetin. Isorhamnetin showed a similar pharmacokinetic pattern in both plasma and liver.
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DISCUSSION |
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TOPABSTRACTMETHODS AND MATERIALSRESULTSDISCUSSIONLITERATURE CITED |
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25 other redox compounds (Fig. 1), likely flavonoids or related polyphenolics, such as glycosides of quercetin, kaempferol, isorhamnetin, and naringenin as well as protocatechuic acid, vanillic acid, and p-hydroxybenzoic acid (10,11). The complex of ASF effectively increased the resistance of human LDL to oxidation in vitro in a dose-dependent fashion within physiologically relevant concentrations (Fig. 2) (26). These results are consistent with several reports of the antioxidant activity of flavonoids such as catechin and quercetin with concentrations administered ranging from 0.25 to 10 µmol/L (35–37). In contrast, Filipe et al. (38) reported a prooxidant activity of low concentrations of quercetin (<2 µmol/L) indicated by increased malondialdehyde formation during Cu2+-induced LDL oxidation. If a prooxidant action of quercetin occurred in our study, it may have been masked by other constituents of almond skin. It is possible that the potential prooxidant actions of single flavonoids do not occur in natural mixtures of plant polyphenols in which opportunities for recycling oxidized compounds may exist, such as the regeneration of oxidized malvidin 3-glucoside by catechin (39). Such interactions (14,40,41) may also partly account for the synergy between the ASF and vitamins C and E observed here (Fig. 3). Similar synergies were observed between genistein and ascorbic acid (40), oat phenolics and ascorbic acid (2), and quercetin and urate (42). In addition to recycling mechanisms, Hwang et al. (40) suggested that polyphenolics may stabilize the LDL particle structure via an interaction with the apoprotein-B domain. Further, vitamin C may contribute to the synergy by inhibiting the decomposition of lipid peroxides and/or preventing Cu2+ from binding to LDL (40).
Extrapolations about flavonoids from in vitro results are limited because of their relatively poor general bioavailability and extensive biotransformation in vivo (14). The bioavailabilities of selected single catechin and flavonol compounds were reported (14,16,19,43,44), but little information is available regarding the concurrent absorption profile of mixtures. Similar to our finding in hamsters, others found a faster plasma Tmax for catechin than quercetin when single compounds were fed to rats (16,44), suggesting that catechin is rapidly absorbedin the upper gastrointestinal tract and cleared from plasma within several hours. In contrast to a Tmax of 120 min for epicatechin in hamsters (Fig. 5), Baba et al. (44) reported a 60-min value in rats. However, caution is warranted when interpreting these values due to pharmacokinetic differences between species as well to other confounding variables such as differing ingredients in the diet fed and potential competition between polyphenolics for absorption (44). In addition, glycoside moieties appear to have a substantial influence on pharmacokinetics, e.g., quercetin-4'-glycoside and rutin (quercetin rutinoside) have Tmax of 0.5 and 7 h, respectively, in humans (26). We observed a Tmax at 180 min for the 3 almond skin flavonol aglycones after deconjugation by glucuronidase and sulfatase in hamsters (Fig. 5), suggesting the potential contribution to this value from unidentified flavonol glycosides in almond skins, such as quercetin, isorhamnetin, and kaempferol glycosides (10,11). Similar to the relations suggested by Manach et al. (13) for humans, we found a shorter half-life in plasma for the catechins compared with the flavonols in hamsters. The half-life of flavonols in the hamsters (5 h) was shorter than that in rats (11–28 h), although such differences could be accounted for by differences in their glycosides (12).
The plasma pharmacokinetics of the almond flavonols were similar with high correlation coefficients (Table 1). Although isorhamnetin is a metabolite of quercetin (45), the association between their plasma concentrations was low, possibly due to direct contribution of isorhamnetin from almond skins. No association was noted between the plasma concentrations of the 2 catechins.
Although the number of reports is limited, flavonoids were detected in mouse and rat tissues with concentrations from 30 to 3000 ng aglycone equivalents/g (13). In hamsters, after ASF gavage, the 2 catechins and 3 flavonols were detected in liver although, with the exception of isorhamnetin, their pharmacokinetic patterns were quite different from those in plasma (Fig. 6). Noticeable amounts of catechin, quercetin, and kaempferol in hamster liver may be attributed to their presence in the basal nonpurified diet fed to hamsters. It is not clear why ASF administration did not increase catechin, epicatechin, kaempferol, or quercetin in the liver, although it is possible that these flavonoids were quickly redistributed to other tissues. Manach et al. (14) reported that >90% of catechin and quercetin in rat liver was methylated. Similar to their relation in plasma (Table 1), quercetin and kaempferol concentrations in the liver were correlated. Although isorhamnetin status in plasma was correlated with its concentration in liver, it was not associated with other hepatic flavonols. The relatively high level of isorhamnetin in liver may reflect a slow rate of clearance compared with other flavonoids or a gradual contribution from methylation of aglycone and glycone quercetin. The increase in hepatic catechins, especially epicatechin, at 300 min may reflect an unusually slow distribution to this tissue or result from the small sample size employed at this one time point.
Consistent with the antioxidant capacity of almond skins using the LDL oxidation assay, Halvorsen et al. (46) demonstrated the antioxidant potency of whole almonds in vitro with the ferric reducing antioxidant power assay, although the vitamin E content of the nut may have contributed substantially to this result. In vivo, a very modest antioxidant effect of ASF was suggested by the small increase in the resistance of LDL in hamsters treated with the almond skin extract compared with saline. Although a higher dose may have produced a greater effect, the weak direct response elicited in vivo may be a result of a lower potency of glucuronidated, sulfated, and/or methylated metabolites of the ASF. Indeed, Moon etal. (47) and Cren-Olive et al. (48) both reported that conjugated derivatives of quercetin and catechin provided less antioxidant protection than their parent compounds against LDL oxidation in vitro. Further, many flavonoid metabolites appear bound to plasma proteins in vivo; thus, they may be less available to interact with LDL (16,20). Nonetheless, despite a weak effect of ASF on the resistance of LDL to oxidation ex vivo, its antioxidant action was strengthened by their synergy with the vitamin E added in vitro in this experiment. A similar synergistic relation was observed between oat phenolics and vitamin C in the same hamster model (2). Interestingly, the ASF-vitamin E synergy appeared in LDL collected at 60 min, the Tmax for catechin, rather than at 180 min, when the greatest concentration of flavonols was obtained. It may be attributed to the more potent antioxidant activity of catechin against copper-induced LDL oxidation than quercetin (49).
In summary, ASF possess antioxidant capacity and interact with vitamins E and C in a synergistic manner to protect LDL against oxidation in vitro. Of the 5 identified flavonoids in the ASF, all appeared in plasma and liver after oral administration. These flavonoids and/or related compounds in the ASF slightly enhanced the resistance of hamster LDL against ex vivo Cu2+-induced oxidation, and their antioxidant capacity was amplified with the in vitro addition of vitamin E. Because almonds represent one of the richest dietary sources of vitamin E, further research is warranted examining the relations between the natural ingredients in this whole food and their potential association with health benefits, such as a reduction in the risk of cardiovascular disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the USDA Agricultural Research Service under Cooperative Agreement No. 58-1950-4-401 and the Almond Board of California. The contents of this publication do not necessarily reflect the views or policies of the USDA nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
4 Abbreviations used: Cmax, maximal concentration; ECD, electrochemical detection; GAE, gallic acid equivalents, Tmax, time to maximal concentration.
Manuscript received 13 January 2005. Initial review completed 27 February 2005. Revision accepted 23 March 2005.
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