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Division of Human Nutrition and Epidemiology, Wageningen University, 6700 EV Wageningen, The Netherlands and * State Institute for Quality Control of Agricultural Products (RIKILT), 6700 AE, Wageningen, The Netherlands
2To whom correspondence and reprint requests should be addressed. E-mail: margreet.olthof{at}staff.nutepi.wau.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • phenolic compounds • chlorogenic acid • caffeic acid • absorption • ileostomy • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and antioxidants might protect against cardiovascular disease.
A major class of phenolic compounds are hydroxycinnamic acids, which
are found in almost every plant (2
,3)
. The major
representative of hydroxycinnamic acids is caffeic acid, which occurs
in foods mainly as an ester with quinic acid called chlorogenic acid
(5-caffeoylquinic acid) (Fig. 1
). Coffee is a major source of chlorogenic acid in the human diet; daily
intake in coffee drinkers is 0.5–1 g; coffee abstainers will usually
ingest < 100 mg/d. Other dietary sources of chlorogenic acid
include apples, pears, berries, artichoke and aubergines
(4)
. Knowledge concerning the absorption of chlorogenic
acid in humans is essential to evaluate possible health effects in vivo
because the absorbed fraction of chlorogenic acid will enter into the
blood circulation and thus can induce biological effects in the blood
circulation. Furthermore, the fraction that is not absorbed will enter
into the colon where it might have biological effects. Chlorogenic acid
and caffeic acid are antioxidants in vitro (1
,5)
, and they
might inhibit the formation of mutagenic and carcinogenic N-nitroso
compounds because they are inhibitors of the N-nitrosation reaction
in vitro (6)
. Further, chlorogenic acid can inhibit DNA
damage in vitro (7
,8)
. Therefore, the inverse association
between coffee intake and colon cancer in some epidemiologic studies
(9
10
11
12
13)
might be explained in part by the chlorogenic acid
present in coffee. However, there are no data on absorption of
chlorogenic acid or caffeic acid in humans. The major problem in
measuring the absorption of chlorogenic acid and caffeic acid in humans
is their bacterial degradation in the colon (14)
. Thus,
measurement of fecal excretion of chlorogenic acid and caffeic acid
would lead to an overestimation of the amount absorbed. Therefore, we
determined the absorption of chlorogenic acid and caffeic acid in
healthy ileostomy subjects, who lack a colon. Ileostomy subjects were
successfully employed previously to determine the absorption of
flavonoids (15)
, coffee diterpenes (16)
and
dietary polysaccharides (17)
.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study was approved by the Ethical committee of the Division of
Human Nutrition and Epidemiology. We recruited subjects by approaching
volunteers who had participated in previous studies at our division
(15
,16)
. Exclusion criteria were as follows: signs of
diseases related to the gastrointestinal tract; resection of > 50
cm of the terminal ileum; an ileostomy that did not function properly;
use of drugs that influenced gastrointestinal transit; present illness;
pregnancy or lactation. Four women and three men, with a mean age of
63 y (range: 46–74 y), and a mean body mass index of 27.1
kg/m2 (range 23.3–34.9 kg/m2) were admitted to
participate and signed an informed consent form. All subject had had a
total colectomy between 7 and 27 y ago for ulcerative colitis or
polyposis coli. The subjects were healthy, based on a medical
questionnaire, normal blood values for hemoglobin, hematocrit and white
blood cell counts, and absence of glucose and protein in urine.
Study design and supplements.
Subjects followed a diet that was low in chlorogenic acid and quercetin
from d 1 to 14. The diet was low in quercetin because one of the
supplements we tested was quercetin-3-rutinoside. To ensure adherence
to the dietary guidelines, we gave the subjects a list of forbidden
foods and beverages. Foods were prohibited if they contained > 15
mg/kg of quercetin or chlorogenic acid. Beverages were prohibited if
they contained > 4 mg/L of quercetin or chlorogenic acid
(4
,18
,19)
. Because subjects were not allowed to drink
coffee and tea during the study, we supplied coffee and tea
substitutes. The coffee substitute was an extract made of chicory, rye
and barley ("Swiss coffee-like," Tayala AG, Birsfelden,
Switzerland) and the tea substitute was an extract of a mixture of
herbs ("Droommix," Piramide, Veenendaal, The Netherlands). We
analyzed the coffee substitute and tea substitute for quercetin and
chlorogenic acid, and the amounts were within the range of the dietary
guidelines (results not shown). Compliance with the dietary guidelines
was good. None of the subjects reported consumption of any foods or
beverages that were on the list of forbidden foods and beverages during
the study. Furthermore, the low chlorogenic acid and caffeic acid
excretion in presupplement ileostomy effluent confirmed that subjects
adhered to the dietary guidelines (Table 1
).
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Collection of ileostomy effluent and urine.
On d 5, 6, 10 and 14, subjects collected one sample of ileostomy effluent and urine just before ingestion of the supplements. After ingestion of the supplements, they collected ileostomy effluent and urine during 24 h. During the daytime, they changed the ileostomy bags every 2 h and immediately stored the bags on dry ice to minimize degradation of the contents by residual bacterial flora. At night, subjects had to change the bags as often as possible.
Subjects collected urine in 0.5 mL plastic bottles, with 0.13 g
thymol (# 8167; Merck, Amsterdam, The Netherlands) as a preservative
and stored the bottles with urine on dry ice immediately after voiding.
We checked the completeness of the urine collection by assessment of
recovery of 270 µmol lithium in urine. It was ingested
daily by the subjects as lithium chloride dissolved in 10 mL of tap
water from 7 d before the first urine collection. Lithium chloride
is completely absorbed and 95% is excreted in urine
(20
,21)
. Urinary recovery of lithium was 94 ± 12%
(mean ± SD), indicating good compliance in collecting
urine.
Sample preparation.
The ileostomy bags were kept frozen with liquid nitrogen during
separation of the plastic bags from the contents. The frozen contents
were freeze-dried, ground to pass through an 0.5-mm sieve and
stored at -20°C until analysis. We thawed the urine bottles in a
water bath of 
40°C, pooled and mixed urine per subject and per
supplement day, froze aliquots of urine in liquid nitrogen and stored
the urine samples at -80°C until analysis. We prepared the samples
collected before breakfast (presupplement sample) and the final
collection at the end of the 24-h collection period (final sample)
separately.
Incubation of chlorogenic acid and caffeic acid with gastrointestinal fluids.
To check for degradation of chlorogenic acid and caffeic acid in
gastrointestinal fluids, we incubated them in vitro in gastric juice
and duodenal fluid, and ex vivo in ileostomy fluid. We incubated 30 mg
of chlorogenic acid and 15 mg of caffeic acid with 3 mL human gastric
juice and 9 mL of water at 37°C for 0.5 and 2 h
(22
,23)
. Similar amounts were incubated with 3 mL human
duodenal fluid and 9 mL water at 37°C for 1 and 4 h,
corresponding to the average and maximal transit time in the small
intestine (24
,25)
. Gastric juice and duodenal fluid were
obtained from two fasted healthy volunteers with a colon and stored at
-20°C.
We also studied the stability of chlorogenic acid and caffeic acid ex
vivo during collection of ileostomy fluid and during sample preparation
in the laboratory. For this purpose, two ileostomy subjects, who also
participated in this study, followed a diet low in chlorogenic acid and
quercetin for 4 d. On d 4, they applied three ileostomy bags in
total, one bag with 300 mg chlorogenic acid mixed with 5 g of
strawberry jam, one with 150 mg caffeic acid mixed with 5 g of
strawberry jam and one with 5 g of strawberry jam only. Strawberry
jam was used as a vehicle for chlorogenic acid and caffeic acid powder.
Strawberry jam itself does not contain chlorogenic acid or caffeic
acid. The subjects allowed ileostomy fluid to drain into the bag for
2 h and kneaded the contents regularly. The ileostomy fluids were
stored and analyzed as described.
Analysis of chlorogenic acid and caffeic acid in ileostomy effluent and urine.
Chlorogenic acid and caffeic acid in ileostomy effluent were extracted
simultaneously by mixing 0.500 g freeze-dried effluent with 25 mL
40% (v/v) aqueous methanol containing 2 g
tert-butylhydroxyquinone/L. The effluent extract was
refluxed at 90°C for 1 h with regular swirling, allowed to cool
down and subsequently brought to 50 mL with methanol. The effluent
extract was then sonicated for 5 min and filtered through a
0.45-µm filter for organic solvents (Acrodisc CR PTFE;
German Sciences, Ann Arbor, MI) before HPLC injection. For HPLC
analysis, we injected 20 µL of the effluent extract
onto an Inertsil ODS-2 (GL Sciences, Tokyo, Japan) column (4.6 x 150 mm, 5 µm particle size) protected by an MPLC
Newguard RP-18 (Brownlee; Applied Biosystems, San Jose, CA) column (3.2
x 15 mm, 7 µm particle size) using
acetonitrile/0.025 mol/L phosphate buffer, pH 2.4 (8:92) as the mobile
phase, at a flow rate of 1 mL/min. The columns were placed in a column
oven set at 40°C. Ultraviolet absorption was measured at 325 nm.
Excretion of chlorogenic acid was calculated as the sum of the
excretion of 3-caffeoylquinic acid, 4-caffeoylquinic acid and
5-caffeoylquinic acid in ileostomy effluent (Fig. 2
). Isomers of chlorogenic acid were produced by incubation of a solution
of 5-caffeoylquinic acid (pH 8) at 100°C for 30 min
(26)
. The limit of detection, i.e., the concentration
producing a peak height three times the standard deviation of the
baseline noise, was 3 µg/g freeze-dried ileostomy
effluent.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Of the ingested chlorogenic acid, 67% was
excreted in ileostomy fluid, whereas only 5% of the caffeic acid was
excreted (Table 1)
. Traces of the ingested chlorogenic acid and 11% of
the ingested caffeic acid were excreted in urine (Table 2
).
|
). Thus, the amounts not excreted in ileostomy effluent were likely
absorbed rather than degraded in the gut or in the ileostomy bag. The
absorption of chlorogenic acid therefore equaled 100% - 67% = 33%
and that of caffeic acid 95%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However,
because the recovery in urine was not nearly complete, chlorogenic acid
and caffeic acid are probably metabolized extensively into other
compounds after absorption. Unfortunately, data on metabolism of
chlorogenic acid and caffeic acid in the human body are scarce. Validity of ileostomy model.
We measured absorption as the difference between the amount of
supplement ingested and the amount excreted in ileostomy fluid in
subjects without a colon. Absorption of nutrients in the small
intestine of ileostomy subjects is probably not affected by the lack of
the colon (29)
, as indicated by their normal serum
cholesterol concentrations (30)
, normal absorption of
para-aminobenzoic acid (15)
and of lithium in
this study (20
,21)
.
It is unlikely that appreciable amounts of chlorogenic acid or caffeic
acid disappeared through degradation in the gastric juice, duodenal
fluid, in the ileostomy bag or during analysis on the laboratory
because chlorogenic acid and caffeic acid were recovered completely
after in vitro and ex vivo incubations in gastrointestinal fluids
(Table 3)
. However, we cannot exclude that part of the supplements were
lost somewhere in the gastrointestinal tract; therefore, the absorption
values we found in this study should be regarded as maximum absorption
values rather than as fixed absorption values. In subjects with a
colon, absorption of dietary phenolic compounds and their metabolites
in the colon is possible. Therefore, in subjects with a colon, caffeic
acid in urine might originate from dietary chlorogenic acid.
Collection of ileostomy effluent.
The amounts of caffeic acid and chlorogenic acid that were not recovered in ileostomy effluent cannot be explained by loss of ileostomy effluent. None of the subjects reported loss of ileostomy effluent during the 24-h collection periods, and the 9–11 ileostomy bags that subjects collected during 24 h also indicated that they had collected all ileostomy effluent. Therefore, we conclude that collection of ileostomy effluent was complete.
The subjects in this study collected ileostomy effluent for 24 h,
which should be long enough to detect all nonabsorbed supplement in
ileostomy effluent because the mean transit time through the stomach
and small intestine is 8–11h (31
,32)
. This was also
supported by the fact that the amount of chlorogenic acid and caffeic
acid excreted in the final collection of ileostomy effluent at the end
of the 24-h period was similar to that in the presupplement collection
(Table 1)
. Furthermore, the recovery of 84 ± 19% (mean ± SD) of quercetin in ileostomy effluent during 24 h
after ingestion of quercetin-3-rutinoside in this study was similar to
the recovery during the first 13 h in a previous study
(15)
.
Comparison with previous studies.
We found that the absorption of caffeic acid esterified with quinic
acid (chlorogenic acid) is three times lower than that of caffeic acid
itself. To our knowledge, there are no previous quantitative data on
absorption of chlorogenic acid and caffeic acid in humans. The studies
that were done on absorption of chlorogenic acid and caffeic acid
measured the recoveries of these compounds and their metabolites in
urine of rats (33
,34)
.
We recovered 0.3% of chlorogenic acid in urine after ingestion. After
ingestion of chlorogenic acid by rats, no chlorogenic acid was found in
urine (35)
. We recovered 11% of caffeic acid in urine
after ingestion, which was comparable to the recovery of 13% found by
(34)
after ingestion of caffeic acid in rats. After
intravenous injection of chlorogenic acid and caffeic acid in rats,
only 9% of chlorogenic acid and 26% of caffeic acid were recovered in
urine (35)
. This indicates that the fraction of
chlorogenic acid and of caffeic acid that is absorbed is metabolized
extensively in the body and therefore only small amounts are recovered
in urine.
Mechanisms of absorption.
The absorption of caffeic acid esterified with quinic acid (chlorogenic
acid) was less than that of caffeic acid itself. It is possible that
chlorogenic acid and caffeic acid are absorbed through different
absorption mechanisms. We can envisage two mechanisms for the
absorption of chlorogenic acid in humans. The first mechanism might
involve absorption of chlorogenic acid as an intact molecule as
indicated by the presence of traces of chlorogenic acid in urine after
ingestion of chlorogenic acid in our study. We probably found only
traces of the absorbed chlorogenic acid in urine because chlorogenic
acid is metabolized intensively after absorption (35)
. The
second mechanism might involve hydrolysis of chlorogenic acid in the
stomach and/or small intestine into caffeic acid and quinic acid before
absorption. The caffeic acid moiety and the quinic acid moiety are
subsequently absorbed (36
,37)
. If this mechanism plays a
role in the absorption of chlorogenic acid, we would expect to find
caffeic acid in urine as we found after intake of the caffeic acid
supplement. If we assume that the absorption of chlorogenic acid is
33% and the amount of caffeic acid in urine after ingestion of caffeic
acid is 11%, then we would expect to recover 4% of chlorogenic
acid in urine as caffeic acid. However, we found only 0.3% of
chlorogenic acid as caffeic acid in urine after ingestion of
chlorogenic acid, which is 10 times lower than we expected. This
indicates that hydrolysis of chlorogenic acid in the stomach or small
intestine is not very important. This is also supported by the fact
that we found a large amount of the ingested chlorogenic acid unchanged
in ileostomy effluent. Thus, this second mechanism likely does not play
an important role in the absorption of chlorogenic acid. Therefore, we
propose that in ileostomy subjects, most of the absorbed chlorogenic
acid is absorbed intact and is metabolized extensively in the liver.
Caffeic acid is probably absorbed through different absorption
mechanisms than chlorogenic acid. We can envisage two mechanisms for
the absorption of caffeic acid in humans. The first mechanism for
absorption of caffeic acid might involve passive absorption of caffeic
acid in the stomach. This is supported by the fact that caffeic acid
and the structurally related compound cinnamic acid were rapidly
absorbed in rats (38)
. Further, in the acid environment of
the stomach, caffeic acid will be primarily in the nonionic form, which
can be absorbed by passive nonionic diffusion. Passive absorption in
the small intestine is not very likely because at a pH of 7 in the
small intestine, caffeic acid will be mainly in the ionic form, which
is difficult to absorb by passive diffusion (39)
. The
second mechanism for absorption of caffeic acid might involve
absorption by an active transport mechanism in the small intestine.
Results from in vitro studies indicate that in the small intestine, an
active Na+-dependent transport mechanism might be involved in the
absorption of cinnamic acids such as caffeic acid (39
,40)
.
Both mechanisms, passive absorption in the stomach and active
absorption in the small intestine, might play a role in the absorption
of caffeic acid in humans.
Chlorogenic acid, caffeic acid and health.
The absorbed fraction of chlorogenic acid and caffeic acid and its
metabolites might induce biological effects in the blood circulation.
Chlorogenic acid and caffeic acid inhibit oxidation of LDL in vitro
(41
,42)
and might therefore protect against cardiovascular
disease. There are no in vivo data available that show that chlorogenic
acid is present in the blood circulation after ingestion, but caffeic
acid is present in blood after ingestion by rats (34)
. In
our human study, we did find chlorogenic acid and caffeic acid in
urine, which also suggests that a small part will be present as such in
blood. We did not measure chlorogenic acid and caffeic acid in blood
because we did not have an available method of analysis.
The fraction of chlorogenic acid that escapes absorption is present
throughout the whole gastrointestinal tract, where it might induce
biological effects. Chlorogenic acid and caffeic acid are antioxidants
in vitro (1
,5)
, and they might inhibit the formation of
mutagenic and carcinogenic N-nitroso compounds (6)
.
Further, chlorogenic acid can inhibit DNA damage in vitro
(7
,8)
. Therefore, chlorogenic acid, the major phenolic
compound in coffee, might be involved in the inverse association
between coffee consumption and colon cancer that was found by some
epidemiologic studies (9
10
11
12
13)
, but not all
(43)
. Thus the one third of ingested chlorogenic acid that
is absorbed could have biological effects in the blood circulation, and
the fraction of chlorogenic acid that is not absorbed could have
biological effects in the colon in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received June 1, 2000. Initial review completed July 24, 2000. Revision accepted September 27, 2000.
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 H. Y. Qiao, J. P. Dahiya, and H. L. Classen Nutritional and Physiological Effects of Dietary Sinapic Acid (4-Hydroxy-3,5-Dimethoxy-Cinnamic Acid) in Broiler Chickens and its Metabolism in the Digestive Tract Poult. Sci., April 1, 2008; 87(4): 719 - 726. [Abstract] [Full Text] [PDF]
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 S. Guglielmetti, I. De Noni, F. Caracciolo, F. Molinari, C. Parini, and D. Mora Bacterial Cinnamoyl Esterase Activity Screening for the Production of a Novel Functional Food Product Appl. Envir. Microbiol., February 15, 2008; 74(4): 1284 - 1288. [Abstract] [Full Text] [PDF]
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 L. F. Andersen, D. R Jacobs Jr, M. H Carlsen, and R. Blomhoff Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Health Study Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1039 - 1046. [Abstract] [Full Text] [PDF]
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S. Lafay, A. Gil-Izquierdo, C. Manach, C. Morand, C. Besson, and A. Scalbert Chlorogenic Acid Is Absorbed in Its Intact Form in the Stomach of Rats J. Nutr., May 1, 2006; 136(5): 1192 - 1197. [Abstract] [Full Text] [PDF]
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 B. Yang, Z. Meng, J. Dong, L. Yan, L. Zou, Z. Tang, and G. Dou METABOLIC PROFILE OF 1,5-DICAFFEOYLQUINIC ACID IN RATS, AN IN VIVO AND IN VITRO STUDY Drug Metab. Dispos., July 1, 2005; 33(7): 930 - 936. [Abstract] [Full Text] [PDF]
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C. Manach, G. Williamson, C. Morand, A. Scalbert, and C. Remesy Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies Am. J. Clinical Nutrition, January 1, 2005; 81(1): 230S - 242S. [Abstract] [Full Text] [PDF]
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 L. Hoffmann, S. Besseau, P. Geoffroy, C. Ritzenthaler, D. Meyer, C. Lapierre, B. Pollet, and M. Legrand Silencing of Hydroxycinnamoyl-Coenzyme A Shikimate/Quinate Hydroxycinnamoyltransferase Affects Phenylpropanoid Biosynthesis PLANT CELL, June 1, 2004; 16(6): 1446 - 1465. [Abstract] [Full Text] [PDF]
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C. Manach, A. Scalbert, C. Morand, C. Remesy, and L. Jimenez Polyphenols: food sources and bioavailability Am. J. Clinical Nutrition, May 1, 2004; 79(5): 727 - 747. [Abstract] [Full Text] [PDF]
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J. Shearer, A. Farah, T. de Paulis, D. P. Bracy, R. R. Pencek, T. E. Graham, and D. H. Wasserman Quinides of Roasted Coffee Enhance Insulin Action in Conscious Rats J. Nutr., November 1, 2003; 133(11): 3529 - 3532. [Abstract] [Full Text] [PDF]
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M. R. Olthof, P. C. H. Hollman, M. N.C.P. Buijsman, J. M. M. van Amelsvoort, and M. B. Katan Chlorogenic Acid, Quercetin-3-Rutinoside and Black Tea Phenols Are Extensively Metabolized in Humans J. Nutr., June 1, 2003; 133(6): 1806 - 1814. [Abstract] [Full Text] [PDF]
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M.-P. Gonthier, M.-A. Verny, C. Besson, C. Remesy, and A. Scalbert Chlorogenic Acid Bioavailability Largely Depends on Its Metabolism by the Gut Microflora in Rats J. Nutr., June 1, 2003; 133(6): 1853 - 1859. [Abstract] [Full Text] [PDF]
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R. Bugianesi, G. Catasta, P. Spigno, A. D'Uva, and G. Maiani Naringenin from Cooked Tomato Paste Is Bioavailable in Men J. Nutr., November 1, 2002; 132(11): 3349 - 3352. [Abstract] [Full Text] [PDF]
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C. Felgines, O. Texier, C. Besson, D. Fraisse, J.-L. Lamaison, and C. Remesy Blackberry Anthocyanins Are Slightly Bioavailable in Rats J. Nutr., June 1, 2002; 132(6): 1249 - 1253. [Abstract] [Full Text] [PDF]
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M. N. Vissers, P. L. Zock, A. J. C. Roodenburg, R. Leenen, and M. B. Katan Olive Oil Phenols Are Absorbed in Humans J. Nutr., March 1, 2002; 132(3): 409 - 417. [Abstract] [Full Text] [PDF]
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M. S. DuPont, R. N. Bennett, F. A. Mellon, and G. Williamson Polyphenols from Alcoholic Apple Cider Are Absorbed, Metabolized and Excreted by Humans J. Nutr., February 1, 2002; 132(2): 172 - 175. [Abstract] [Full Text] [PDF]
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