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Laboratory of Food and Nutrition, Graduate School of Science and Technology, Chiba University, 648 Matsudo, Matsudo, Chiba 271-8510, Japan
1To whom correspondence should be addressed. E-mail: zhaohuizhao{at}hotmail.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • absorption • ferulic acid • metabolism • stomach • rats
Ferulic acid (FA)2 is one of the most abundant phenolic compounds in the human diet, especially in staple foods (1,2). People may consume 500-1000 mg cinnamates (mainly FA and caffeic acid) daily depending on their dietary habits (1). Many studies have documented the beneficial properties of FA, including its strong antioxidant, free radical–scavenging, and anti-inflammatory activities (3–6). Possibly because of these properties, recent studies suggested that FA could have preventive effects against some chronic diseases, such as Alzheimer’s disease (7,8), diabetes (9,10), and colon cancer (11,12).
As a functional food factor or a potential nutrient supplement, the fate of FA after administration in vivo must be investigated carefully. To date, studies showed that FA could be absorbed in rat intestine (13,14), and orally administered FA has a very high bioavailability in rats (13,15–17). FA is present in plasma and urine mainly as conjugated forms (16). However, the absorption of FA in the stomach remains unknown. Moreover, the site of metabolism of FA has not been identified, although the liver and small intestine are the major organs of metabolism of xenobiotics (18). When free FA was transported across the isolated small intestinal section, 
20% of the FA was conjugated with glucuronide and/or sulfate (14), suggesting that FA could be metabolized in the intestinal epithelial cells. Such a suggestion, however, was not supported by the results of a recent study using the human colon adenocarcinoma cell line Caco-2 (19). We showed that a considerable amount of FA was recovered in rat plasma only 5 min after its oral administration (16). At the 5-min time point, the proportion of free FA to total FA in the plasma was very high (34 ± 13%); it decreased quickly thereafter, however, whereas the proportion of conjugated FA increased. We presumed therefore that FA might also be absorbed in the stomach, and that the absorbed FA might be conjugated principally in liver and/or other tissues but not in gastrointestinal epithelial cells.
The present study was designed to test the hypothesis by determining the recovery of FA and its metabolites in rat gastric content, gastric mucosa, portal vein plasma, celiac arterial plasma, bile, and urine after the incubation of free FA in situ in rat stomach for 25 min. Because 5-O-feruloyl-L-arabinofuranose (FAA, a FA sugar ester, Fig. 1) is the most common form of FA in cereals (1,16,20), its absorption in rat stomach was also investigated for comparison. The same metabolites (FA-glucuronide/sulfates) of dietary FA as those in rat urine were found to exist in human urine (21,22), indicating that rats could be used as a model for studying the absorption and metabolism of dietary FA in humans. Therefore, the results of this work will contribute to understanding the metabolism of dietary FA in humans and consequently, the physiologic functions of dietary FA in the prevention of chronic diseases.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animals and diets. Wistar male rats (n = 24; 7 wk old) from CLEA Japan were housed in an air-conditioned room (22 ± 2°C), with a dark period from 1900 to 700 h. They had free access to water but food was available only during the dark period for the whole experimental period (16). The rats were fed a standard purified diet (17) for 7 d and thereafter divided into 6 groups by body weight (BW) before the experiments. The care and treatment of the rats were conducted according to the guidelines prescribed by the Faculty of Horticulture, Chiba University.
In situ gastric absorption. The method was a modification of the one of Barr and Riegelman (24), which was used for the study of in situ intestinal drug absorption. After the rats were food deprived for 8 h (to eliminate the influence from the chyme residue in the stomach), they were anesthetized with sodium pentobarbital and kept alive under anesthesia throughout the experiments. At first, the pylorus was ligated, and then 2.25 µmol FA (8 µmol/kg BW, in situ FA-experiment group), or FAA (in situ FAA-experiment group) in 0.5 mL physiological saline at 37°C, or vehicle alone (in situ control group) was injected into the stomach through the cardia by a syringe with plastic tubing. Immediately after, the cardia was also ligated (Fig. 2). Second, the biliary duct was cannulated. It took 3.6 ± 0.2 min (n = 12) from the beginning of the administration to the end of biliary duct cannulation. Bile was collected for up to 25 min after the administration. During the whole experimental period, the rats were kept at 37°C by warming with a filament lamp and tissue papers soaked with 38°C physiological saline. At 25 min postadministration, blood was withdrawn with heparinized syringes from the portal vein and the celiac artery, respectively. Thereafter, the whole stomach was removed and immediately placed on ice (0°C). Urine was withdrawn from the bladder. Last, the rats died from blood loss under anesthesia. The gastric contents and mucosa were washed 4 times with 3 mL of physiological saline. The washing solution was pooled and the volume was adjusted to 14 mL for the determination of the FA or FAA in gastric content. The washed gastric mucosa was homogenized and extracted with 4 mL of physiological saline for the determination of the FA or FAA in gastric mucosa. All of the treatments for extracting gastric content and mucosa were carried out at 0°C. All samples were stored frozen at –30°C until required for analysis.
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It should be mentioned that we did not determine the effects of anesthesia on the metabolism of FA. However, both the metabolites and their proportions detected in the urine of rats under anesthesia (in this study) were similar to those of normal rats (16).
In vitro gastric absorption. To confirm the reliability of the method used for evaluating the recoveries of FA and FAA in gastric contents and mucosa in the in situ experiment, in vitro experiments for gastric absorption were also carried out with the isolated rat stomach. The whole stomach was removed from anesthetized rats. After the stomach was cooled for 20 min on ice (0°C), 2.25 µmol FA, or FAA in 0.5 mL physiological saline, or vehicle alone was injected into the stomach and incubated for 25 min. The extracts of gastric contents and mucosa were prepared by the same procedure as described above in the in situ experiment. To determine whether FA and FAA can physically diffuse across the gastric mucosa and also to eliminate the influence of unexpected biological reactions, the temperature of the experimental environment was kept at 0°C by using ice water in the experiment on in vitro gastric absorption.
Determination of FA in gastric contents and mucosa. The method was modified from one used in a previous study (16). Briefly, after the supernatant of the gastric contents or the mucosa extract was treated with distilled water (for determining the free FA) or ß-glucuronidase type H-2 solution (for determining the total FA), the FA was determined with HPLC analysis.
Determination of FAA in gastric contents and mucosa. The same method was used for determination of FAA in gastric samples as that for determination of FA except that the total FAA was quantified as free FA after the samples were hydrolyzed with NaOH aqueous solution as previously described (16,17).
Determination of free FA and its metabolites in plasma, urine, and bile. Free FA and its metabolites in the plasma, urine, and bile were determined with HPLC after the sample were prepared by the use of combined enzymatic hydrolysis as previously described (16).
HPLC analysis. An L-7100 intelligent pump (Hitachi), Nova-Pak C18 column (4.6 x 250 mm; Waters Chromatography Division/Millipore) with a guard column and UV detector system (Hitachi) were used for HPLC analysis. The conditions for HPLC analyses were the same as those described previously (16). Identification of the compounds was confirmed by comparing retention times and absorption spectra with those of standard materials. Quantification was accomplished using calibration of the FA standard. The calibration curves were made by analysis of the blank samples (gastric content and mucosa extract, plasma, urine, and bile from the in situ control group) spiked with a series of concentrations of standard FA.
Statistical analysis. Data are shown as means ± SD (n = 4). For the proportion data in Table 2, Tukey’s multiple-range test was used when significant differences (P < 0.05) were obtained by one-way ANOVA. The difference of the recoveries of FA in the gastric content and mucosa between in situ and in vitro experiments was tested with using a t test (two-sample assuming equal variances, Microsoft Excel).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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After 2.25 µmol of FA was incubated in rat stomach in vitro for 25 min, 80 ± 6% of the incubated FA was detected in the gastric contents (Table 1). By contrast, after the FA was incubated in rat stomach in situ, only 26 ± 11% of the incubated FA was detected in the gastric contents. In both groups, an appreciable amount of FA (7 ± 1 and 4 ± 2% of incubated FA, respectively) was also detected in the mucosa. The recoveries of FAA in the gastric contents also differed significantly between the in situ and in vitro experiments although the difference was not as great as that of FA (Table 1).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Because dietary FA commonly exists as FAA, a FA sugar ester, we also determined the gastric absorption of FAA. After the FAA was incubated in rat stomach, its recovery in the gastric contents in situ was significantly lower than that in vitro (Table 1). This indicated that FAA might also be absorbed in rat stomach, although its absorption rate was rather low compared with that of FA (Table 1). In agreement with earlier results (17), FAA seemed to be absorbed gradually along the gastrointestinal tract up to the cecum. Orally administered FAA might therefore provide a lasting and possibly appropriate plasma concentration of FA (16), which might be more beneficial for developing the physiologic effects of dietary FA. Although many studies focused on methods to extract and refined pure FA from foodstuffs and then use it as a nutrient supplement, we propose, given the findings of this study, that it may be better to ingest FA in its natural bond form (e.g., sugar ester form).
It was reported that other flavonoids, such as quercetin, daidzein, and genistein, could be absorbed from the rat stomach (26,27). More recent studies showed that the glycosides of anthocyanins could be also absorbed from rat stomach (28,29). However, rutin (a glycoside of quercetin) seemed not to be able to be absorbed from the stomach (26).
The absorption mechanism of FA has not yet been established. Several in vitro and in situ studies indicated that FA might be transported across the intestinal epithelial cells by a monocarboxylic acid transporter (19), a Na+-dependent, carrier-mediated transport mechanism (30), passive diffusion, or a facilitated transport mechanism (13). In the present study, the in vitro results (Table 1) indicated that FA could be absorbed into the gastric mucosa cells even at 0°C, suggesting that FA might diffuse quite freely across the stomach mucosa. FA (with pKa = 4) (19) should exist mainly in an undissociated form because of the strong acidic environment of the stomach (pH 1–3). The undissociated FA, i.e., protonated FA, would have a high oil/water partition coefficient; thus, it could be absorbed by passive diffusion according to the pH-partition theory (31). However, we cannot exclude that a monocarboxylic acid transporter might also be involved in the gastric absorption of FA because the gastric absorption rate of FA was very high and the monocarboxylic acid transporter expression was detected in mouse stomach (32).
Metabolic fate of oral administered FA in rats. After free FA was incubated in rat stomach for 25 min, neither conjugated FA nor any other FA derivatives were detected in the gastric contents or mucosa (Fig. 3 and Table 2). This indicated that FA might be absorbed as the free form from rat stomach, and the stomach including its epithelial cells might not metabolize FA. Adam et al. (13) also found that free FA was not changed or metabolized in rat intestine after it was perfused through the small intestine in situ for 30 min. Consistent with these in situ results, Konishi et al. (19) reported that FA was not conjugated when it was transported across Caco-2 cell monolayers. On the contrary, Kern et al. (33) detected a small amount of FA sulfate in the FA-added medium with which the Caco-2 cells had been cultured for 25 h. Similarly, Spencer et al. (14) observed a low level of FA glucuronide after FA was perfused through the jejunum or ileum in an isolated rat intestinal model. From these studies, nevertheless, we may conclude that the gastrointestinal tract is not the major site for metabolizing FA. This differs from the metabolism of other dietary phenolic compounds, such as quercetin and catechin. Studies (34,35) showed that both quercetin and catechin were metabolized extensively in rat intestinal epithelia after their absorption. Moreover, part of the conjugated quercetin appeared to be secreted back into the intestinal lumen (35).
The proportion of free FA to total FA in the portal vein plasma was very high (49 ± 5%, Table 2). However, it declined to 6.2 ± 2.7% after blood reached the arteries (Table 2). Such a change should be derived mainly from the metabolism of FA in the liver and from the biliary excretion, in addition to the effect of the absorption and metabolism in the stomach. We knew that FA was absorbed from the stomach in the free form and transported into the portal vein (Fig. 3 and Table 2). We also knew that the proportion of free FA to total FA in bile was as low as that in arterial plasma (Table 2). Therefore, we can presume that the metabolism of FA in liver is the primary cause for decreasing the proportion of free FA and at the same time for increasing the proportion of conjugated FA to total FA in plasma. In other words, the results of this work demonstrated that FA is metabolized mainly in rat liver. Such a conclusion is supported in part by a recent study (12) showing that 1% FA in the diet could elevate the activity of UDP-glucuronosyltransferase in the hepatic microsome but not in the intestinal microsome of rats.
Considering the fact that as soon as free FA was absorbed, most of it may be metabolized into conjugates in liver and then introduced into the circulation mainly in the conjugated forms, it is important to understand the bioactivities of free FA and its metabolites individually. If only free FA has the proposed physiologic functions in vivo, effective administration methods, e.g., subcutaneous injection, should be selected to avoid the first-pass metabolism by liver and keep a relatively high concentration of free FA in some specific tissue.
Although the proportions of free FA or FA-sulfoglucuronide to total FA did not differ significantly among the celiac arterial plasma, bile, and urine (Table 2), the proportions of FA-glucuronide in bile and urine were significantly higher than that in the circulation (arterial plasma). This indicated that FA-glucuronide might be more easily excreted through bile and urine. It would also suggest that FA might be conjugated in part into FA-glucuronide in kidney.
Within 25 min after FA administration, 4 ± 2% of the administered FA was excreted into bile after it was absorbed and conjugated with sulfate and/or glucuronide in liver. These results are consistent with those of Adam et al. (13) who found that the percentage of biliary secretion was equivalent (5–7% of the perfused dose) irrespective of the amount of the perfused dose of FA in small intestine. In rat cecum, however, neither free FA nor conjugated FA was detected after rats were fed a diet containing 0.15% FA (17), suggesting that the excreted FA through bile might be reabsorbed in the small intestine. That is to say, like some drugs, FA may undergo enterohepatic circulation in rats. This may prolong the presence of FA and its metabolites in the body to some extent.
Under the conditions of this study, 74 ± 11% of administered FA (2.25 µmol) seemed to be absorbed from the stomach within 25 min after the administration. Of the FA absorbed, 4 ± 2% of the dose was stored in the gastric mucosa, and 4 ± 2 and 3 ± 3% of the dose was excreted through bile and urine, respectively. From the concentration of total FA in the plasma, it could be also estimated that 10% of the dose was in the blood pool. At that time, therefore, 53% of the dose might be distributed in liver, kidney, and/or other tissues, where FA may have biological effects. Similarly, Adam et al. (13) also determined that 49% of perfused FA in rat intestine might be distributed in liver and peripheral tissues. In these tissues, a part of FA (free and conjugated FAs) might be metabolized into other phenolic compounds with lower molecular weight, such as vanillic acid and dihydroferulic acid (36,37). Eventually, however, most of the FA would be excreted through urine mainly in the conjugated forms (16).
According to the above discussion, we propose the metabolic fate of free FA administered in rat stomach (Fig. 4). After FA is absorbed as a free form by gastric mucosa cells, it is transported into the portal vein and goes through the liver where it may be conjugated mainly with glucuronide/sulfate. Thereafter, the remaining free FA and conjugated FA enter the systemic circulation and are distributed into peripheral tissues, whereas a fraction of the FA are secreted into bile and then may enter the enterohepatic circulation. A part of the free FA and its conjugates in the systemic circulation and tissues are metabolized into other compounds, whereas most of them are finally excreted through kidney mainly as conjugated FA.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 23 July 2004. Initial review completed 8 August 2004. Revision accepted 27 August 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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