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Laboratory of Food and Nutrition, Graduate School of Science and Technology, Chiba University, 648 Matsudo, Matsudo, Chiba 271-0082, 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: • bioavailability • excretion • ferulic acid ester • metabolism • rat
Ferulic acid (FA) and its dimers are ubiquitous components of cell walls of plants (1 ). Some in vitro and epidemiological studies indicate that FA, as a predominant phenolic acid in cereals, is important in the prevention of chronic disease, such as coronary heart disease and some cancers (2 –5 ).
Almost all FA in cereals is esterified with arabinose or galactose residues in the pectic or hemicellulosic component of cell walls (6 –9 ). In previous studies, 5-O-feruloyl-L-arabinofuranose (FAA), feruloyl-arabinofuranosyl-xylopyranosyl-xylose (a feruloylated oligosaccharide) and feruloyl-arabinoxylan (FAXn) show the same or even stronger antioxidant activity compared with FA in the microsomal lipid peroxidation system or in the LDL autoxidation system (10 ,11 ). It is also reported that a chemically synthesized FA ester (2-methyl-1-butyl FA) markedly suppresses inflammatory responses and skin tumor promotion more than does FA in vitro (12 ).
To completely understand the physiological function of dietary FA, it is necessary to investigate its metabolism, which accounts for the increasing number of studies on the bioavailability of free FA (13 ,14 ) or FA derivatives in foodstuffs (15 –18 ). Most of these studies focus on the absorption and excretion of free FA or total amounts of free and conjugated FA. Only one study investigated FA metabolites in circulation (14 ), but the result of that study is quantitatively quite different from that of a metabolic study on caffeic acid, another kind of hydrocinnamic acid (19 ).
A recent in vitro study established that feruloylated arabinose could be hydrolyzed by tissue extracts from both small and large intestines of rats (20 ); moreover, FA in wheat bran could be recovered in rat urine (18 ). However, there is little information in the literature on the metabolism and excretion of FA sugar esters in vivo.
In this study, we investigated the metabolic derivatives of FA in rat plasma and urine after oral administration of FA, FAA or FAXn to provide pharmacokinetic profiles and bioavailability of the parent compounds in rats.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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FAA and FAXn (Fig. 1A ) were isolated from refined corn bran by acid hydrolysis and gel filtration chromatography (10 ,11 ). ß-Glucuronidase (EC 3.2.1.3 1) type H-2, ß-glucuronidase type B-1 and D-saccharic acid 1,4-lactone were from Sigma Chemical (St. Louis, MO). FA, salicylic acid and other chemicals were of analytical or HPLC grade (Wako Pure Chemical Industries, Osaka, Japan).
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Thirty-six 7-wk-old Wistar male rats from CLEA Japan (Tokyo, Japan) were housed in metabolic cages in an air-conditioned room (22 ± 2°C), with a dark period from 1900 to 0700 h. They were allowed free access to water but to food only in the dark period during the whole experimental period. After 4 d of acclimatization, the rats were fed for 10 d with a standard purified diet based on AIN-76 (21 ). They were divided into nine groups on d 8. On d 10, the first four groups were administered orally (70 µmol FA/kg body) FA, FAA, FAXn (in 2 mL water) or 2 mL distilled water (DW, as control), respectively. Before and after administration, urine and feces were collected at various intervals over 40 h. Another four groups were administered the same materials in the same way as described above for plasma sampling: before and at intervals over 4 h after the administration, blood samples (about 0.5 mL) were collected from the tail vein into heparinized tubes. The ninth group was administered the same dosage of FAXn to collect blood samples at intervals over 4–24 h after administration. Plasma was prepared by centrifuging the blood at 2000 x g for 15 min at 4°C. Urine samples were filtered by filter papers. Feces were lyophilized and ground. All samples were stored frozen at -30°C until required for analysis. The care and treatment of the rats were carried out according to the National Institutes of Health Guide for Care and Use of Laboratory Animals (22 ).
Determination of free FA and its metabolites in plasma and urine.
FA metabolites in plasma and urine were determined by HPLC after samples were prepared by use of combined enzymatic hydrolysis (19 ,23 ,24 ). Plasma or urine (200 µL) was acidified (to pH 5.0) with acetic acid, to which was added 40 µL of 2 mmol/L salicylic acid aqueous solution as internal standard. The solution was then divided into four equal portions. To the first portion, 5 µL of ß-glucuronidase type H-2 solution (with 500 U of ß-glucuronidase and 25 U of sulfatase) was added to determine the amount of all forms of FA (total FA); another 5 µL of the same enzyme solution together with 10 mg D-saccharic acid 1,4-lactone (a ß-glucuronidase inhibitor) was added to the second portion; and 5 µL of ß-glucuronidase type B-1 (500 U) was added to the third portion. All three portions were then saturated with nitrogen gas and incubated at 37°C for 2.5 h (for plasma) or 12 h (for urine). The FA in the incubated solutions was extracted with 0.05 mol/L HCl-ethanol according to the procedure of Azuma et al. (19 ). The fourth portion, to which 5 µL DW was added, was directly extracted with HCl-ethanol to determine the amount of free FA. A 10-µL sample (20 µL if necessary) of the extract was used for HPLC analysis. By this method, the amount of free FA subtracted from that quantified in the second portion was referred to as the amount of FA-sulfate; the amount of free FA subtracted from that quantified in the third portion was referred to as the amount of FA-glucuronide; the amount of free FA, FA-sulfate and FA-glucuronide subtracted from the amount of total FA was defined as the amount of FA-diconjugate, which is conjugated with glucuronide and sulfate (FA-sulfoglucuronide; Fig. 1 B).
Determination of total FA in feces and materials.
The amount of total FA in feces and in materials was determined as the free form by use of HPLC after the sample was hydrolyzed with NaOH aqueous solution according to the method of Shibuya (25 ).
HPLC analysis.
The conditions for HPLC analyses were as follows: pump, L-7100 intelligent pump (Hitachi, Tokyo, Japan); column, Nova-Pak C18 column (4.6 x 250 mm; Waters Chromatography Division/Millipore, Milford, MA) with a guard column; detection, UV at 320 nm; mobile phase, solvent A (20% methanol in 5 mmol/L HCl) and solvent B (acetonitrile) were mixed using a linear gradient apparatus by changing solvent B as follows: 0% (0 min) 
15% (5 min) 25% (15 min) 0% (20 min); flow rate, 1.0 mL/min. Sample identification was confirmed by comparing retention times and absorption spectra to those of standard materials. Quantification was accomplished using calibration of the standards.
Statistical analysis.
Data are shown as means ± SD (n = 4). Tukey’s multiple-range test was used when significant differences were obtained by one-way ANOVA. When variances were unequal, data were log-transformed before ANOVA and reanalyzed. Significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Metabolites in rat plasma from the FAXn-administered group could not be detected separately by the method because of their low concentration. Whether FA or FAA was administered, the plasma extracts gave similar chromatograms (Fig. 2 ). Four peaks were detected when the plasma was not treated with enzymes (Fig. 2 A). Peak 4 was identified as the internal standard and peak 3 was identified as free FA by comparison with authentic standards in HPLC and UV spectra analyses. According to the change of area under the curve (AUC) of peaks after the plasma was hydrolyzed with selective enzymes, peak 1 was referred to as FA-glucuronide and peak 2 was referred to as FA-sulfoglucuronide mixed with a few FA-sulfate and FA-glucuronides. The probable structures of these conjugates are shown in Figure 1 B. It should be noted that the number and position of conjugated moieties must be identified by other methods such as NMR and mass spectrometry.
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No total FA was detected in the plasma of rats after administration of DW. Similar to the time course of the main metabolite [i.e., FA-sulfoglucuronide (Table 1)], total FA concentrations reached their maximum at 15 min for the FA-administered group and at 30 min for the FAA-administered group, and then decreased (Fig. 3 ). The maximum concentration of total FA in the FA-administered group was about 5 times that in the FAA-administered group and about 100 times that in the FAXn-administered group (Table 2). On the other hand, the total FA in plasma from the FA-administered group disappeared very quickly (almost in 120 min), whereas that from the FAA-administered group was 8.3 ± 1.5 µmol/L even at 240 min (Fig. 3) . A low concentration of total FA (0.3 µmol/L) was also detected in the plasma from the FAXn-administered group at 20 h after administration.
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The cumulative urinary excretion of total FA increased with time after administration of FA, FAA or FAXn (Fig. 4 ). The relative increase with time seemed to be biphasic; a rapid elimination phase up to 6 h was followed by a slower 10-h phase for the FA- and FAA-administered groups. For the FAXn-administered group, however, the excretion rate in the second phase was faster than that in the first phase. After the two phases, excretion reached a plateau for all three groups.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Free FA and three FA metabolic derivatives (FA-sulfoglucuronide, FA-glucuronide and FA-sulfate) were detected in rat plasma and urine whether FA or FAA was administered. The concentration of metabolites in plasma from the FAXn-administrated group was too low to detect by HPLC. Nevertheless, the same compounds and similar composition ratio of these compounds were detected in the urine of this group as those found in the other two groups (Table 3). Moreover, we showed that administered FA and its sugar esters were recovered in the circulation mainly as FA-sulfoglucuronide and FA-glucuronide rather than the parent compounds. Thus, the various physiological functions of FA and its sugar esters found in vitro might need to be reconsidered. We previously determined that FA-glucuronide had the same ability as FA to protect LDL oxidation in vitro (26 ). Further studies on the antioxidant activity of FA-sulfoglucuronide should be performed.
Similar to our results, the studies of Piskula and Terao (24 ) and Azuma et al. (19 ) showed that administered epicatechin or caffeic acid are determined in rat plasma mainly as their sulfoglucuronide and glucuronide conjugates, but also as epicatechin-sulfate at relatively low concentration or as the sulfate of methylated caffeic acid but not as caffeic acid-sulfate. However, Rondini et al. (14 ) reported that sulfated FA was the main metabolite after short-term ingestion of free FA in male Sprague–Dawley rats. The authors made no mention of the concentration of FA-sulfate or FA-sulfoglucuronide individually. We contend that the sulfated FA in their study should include FA-sulfate and FA-sulfoglucuronide, in which case comparison of sulfated FA with its glucuronized conjugates (FA-glucuronide and FA-sulfoglucuronide) should be described in the same manner as in the study of Piskula and Terao (24 ). In this way, our results indicate that the glucuronized conjugate, rather than the sulfate conjugate, was the main metabolite in rat plasma and urine. The differences might be attributable to the inconsistency of the rat strains used with metabolic variance.
Metabolic pathway of FA and its esters.
The plasma concentration of total FA in rats was 73.9 ± 22.5 µmol/L at 5 min after FA administration (Table 1). This might partly be a consequence of FA absorption, which occurred in the stomach, similar to that found for quercetin (27 ). Moreover, a high percentage of the free form (34% of the total FA) was present in rat plasma at the beginning (at 5 min after administration), although it decreased very rapidly and almost disappeared in 30 min after FA administration. These results indicated that a considerable amount of FA might quickly be absorbed as the free form and then conjugated in the liver within a short time. In vitro studies have implicated the existence of a Na+-dependent, carrier-mediated transport process in the uptake of free cinnamic acid and structurally related substrates such as FA across the brush border membrane of rat jejunum (28 ,29 ). Another in vitro study suggested that FA is absorbed predominantly as the free form and only 20% of the total amount is predisposed to glucuronidation through both the jejunum and ileum (30 ). Thus, our study seemed to provide in vivo evidence for those suggestions.
That plasma metabolites of administered FAA were the same as those of administered FA (Table 1) suggested that administered FAA might first be broken down into FA at some point and then undergo the metabolic pathway of FA. It is presumed that bound hydroxycinnamates are released from plant cell walls by the resident flora in the hindgut of nonruminants (31 ). However, a considerable concentration of metabolites appeared in rat plasma within only 5–15 min after FAA administration (Table 1). In such a short time, the dosage could not reach the hindgut, so some FAA could be absorbed in the rat small intestine. Twenty-five percent of total metabolites in rat plasma were conjugated FAA after FAA overdosing (11 ). Recently, FAA esterase activity has been found in mucosa from both small and large intestine of rats (20 ). These results, together with our findings, suggested that some FAA could be absorbed directly into small intestinal mucosal cells and then be hydrolyzed and metabolized in tissues. It has been reported that other phenol esters undergo such a metabolic pathway (23 ,32 ).
A low concentration of total FA in plasma (0.3–1.3 µmol/L) was detected from 30 min to 20 h after administration of FAXn. This might happen because absorption of FA from FAXn can occur throughout the gut. FAXn is a mixture of feruloylated sugars that mainly contain a series of fragments of feruloyl-arabinoylated polysaccharide (heteroxylan) and a few feruloylated oligosaccharides (6 ,9 ,11 ,33 ). Thus, after the administration of such a mixture, feruloyl-disaccharide in the mixture could be absorbed and metabolized as the same mode as that of FAA. Other oligosaccharides and those feruloyl-arabinose linking short-chain fragments of heteroxylan could not be absorbed until being hydrolyzed by the microbial flora in the hindgut and those feruloyl-arabinose linking too long chain fragments of heteroxylan may be excreted directly through the feces.
Jacobson et al. (34
) and Teuchy and Van Sumere (35
) reported that FA is metabolized to other phenolic compounds (e.g., vanillic acid or dihydroferulic acid) in rat circulation. 3-Hydroxyphenylpropionic acid derived from FA and caffeic acid is commonly found in the urine in all species (31
). We found that 
27% of administered FA, 45% of FA in administered FAA and 60% of FA in administered FAXn was not recovered in urine or feces as free FA or its conjugated forms (Table 4), so they might be metabolized into the above-mentioned compounds.
Bioavailability of FA and its esters.
The results of high urinary recovery (72%) but no fecal recovery of administrated FA (Table 4) indicated that the bioavailability of FA is very high. These results are similar to those reported by Adam et al. (18
) and Rondini et al. (14
), who indicated that 43–50% of the amount of ingested FA in the diet was recovered in urine. Choudhury et al. (13
) also determined, based on the similarities between oral and intravenous dosing, that free FA has a good bioavailability in rats. Although a large dosage was used in their study (265 µmol/kg body, 3.5 times that used in our study), the results of urinary recovery as the forms of free FA and FA-glucuronide in 24 h after oral administration are very similar to ours (5.4 ± 4.1 vs. 3.2 ± 1.5% for the free form and 5.1 ± 3.6 vs. 4.8 ± 1.7% for the glucuronide form). Subsequently, however, Choudhury et al. (13
) attributed only 10.5% of urinary recovery to the dosage and thus concluded that renal excretion is not a major pathway of elimination for intact hydroxycinnamates, although one might question their method, in which they did not take account other metabolites (e.g., FA-sulfoglucuronide) in urine. The same method was used for determining urinary recovery of FA in tomatoes (15
) and in low alcohol beer (16
) ingested by humans. Because FA-sulfoglucuronide might be the major metabolite in human urine as that in rats’ urine, the urinary recovery of FA in those foods might be higher than that reported.
FA and its esters with equimolar amounts of FA did not lead to the same time course of total FA concentration in rat plasma (Fig. 3) . The total area under the plasma concentration–time curve (AUC) of the FAA group was about 56%, and the AUC of the FAXn group was about 21% that of the FA group (Table 2). These results may verify that the bioavailability of FA sugar esters is lower than that of its free form and that the more complex the molecular structure of FA sugar ester is, the lower its bioavailability should be. It must be noted that the AUC of FAXn was calculated in 20 h rather than 4 h (Table 2) because its metabolites were sustained in plasma for such a long time; however, FA bioavailability from FAXn may be reasonably adequate. Although the total FA concentration in the plasma from the FAXn-administered group was lower than that from the other two groups, concentrations in the 100 nmol/L range are not negligible. Moreover, such concentrations are representative of those usually found for some polyphenols in human plasma. Furthermore, a perdurable and possibly an appropriate concentration might be more beneficial for developing the physiological effect of FA sugar esters. Further studies are thus needed to determine accurately FA metabolites in rats administered FAXn.
In conclusion, we have demonstrated that 1) administered FA and its sugar esters were recovered in rat plasma as the forms of FA-sulfoglucuronide, FA-glucuronide, FA-sulfate and free FA; these compounds are then eliminated as the same forms mainly through the pathway of renal excretion; 2) the bioavailability of FA and its sugar esters is dependent on the absence or presence of a saccharide moiety and, in the latter case, its structure. Such a difference in the molecular structure seems to affect both the site and the mode of their absorption in gut and their ensuing metabolism. We first showed that FA-sulfoglucuronide is the main metabolite in the plasma of rats after administration of free FA or its sugar esters. Thus, the various physiological functions of FA and its sugar esters found in vitro likely should be reconsidered. Further studies on the antioxidant activity of FA-sulfoglucuronide should be performed.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 15 December 2002. Initial review completed 7 January 2003. Revision accepted 14 February 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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