Dig Dis Sci (2008) 53:436–442
DOI 10.1007/s10620-007-9861-x
ORIGINAL PAPER
Decreased Histamine Catabolism in the Colonic Mucosa
of Patients with Colonic Adenoma
Michael A. Kuefner Æ Hubert G. Schwelberger Æ
Eckhart G. Hahn Æ Martin Raithel
Received: 4 August 2006 / Accepted: 30 April 2007 / Published online: 12 June 2007

Springer Science+Business Media, LLC 2007
Abstract
Introduction Alterations in mucosal histamine degrada-
tion play an important role in various gastrotinestinal dis-
eases including colonic adenoma. In humans, histamine can
be catabolized either by oxidative deamination by diamine
oxidase (DAO) or by ring methylation by histamine N-
methyltransferase (HNMT). The significance of HNMT in
this context was investigated for the first time in this project.
Methods About 94 colonic biopsies were endoscopically
obtained from 23 patients suffering from colonic adenoma
and 26 biopsies from six healthy individuals. Each sample
was mechanically homogenized, homogenates were cleared
by centrifugation and used for determination of protein and
histamine concentrations and enzyme activities of DAO and
HNMT by radiometric assay.
Results In adenoma patients DAO activities were slightly
and HNMT activities were significantly decreased in normal
mucosa compared to controls. Activities of both enzymes
were significantly lower in adenoma tissue than in healthy
mucosa in the same patients. A significant correlation was
found between HNMT and DAO in all investigated samples.
Histamine concentrations were elevated in adenoma patients.
M. A. Kuefner (&)
Radiologisches Institut, Universität Erlangen-Nürnberg,
Maximiliansplatz 1, 91054 Erlangen, Germany
e-mail: michael.kuefner@idr.imed.uni-erlangen.de
H. G. Schwelberger
Labor für Theoretische Chirurgie, Universitätsklinik für
Chirurgie, Universität Innsbruck, Schöpfstraße 41, 6020
Innsbruck, Austria
E. G. Hahn
M. Raithel
Funktionelle Gewebediagnostik, Medizinische Klinik I mit
Poliklinik, Universität Erlangen-Nürnberg, Krankenhausstraße
12, 91054 Erlangen, Germany
123
Conclusions Histamine catabolism is decreased in the co-
lonic mucosa of patients with colonic adenoma.
Keywords Histamine N-methyltransferase
Diamine
oxidase
Colorectal adenoma
Histamine metabolism
Introduction
Colorectal cancer represents one of the most frequent
malignancies in industrialized countries. The incidence in
the United States is about 135,000 per year, with 57,000
related deaths in 2001 [1]. The lifetime risk of this tumor
approaches 6% in both men and women [2].
Today several etiologic factors, such as cigarette
smoking, alcohol consumption, nutrition rich in lipids or
red meat, advanced age or genetic factors, are known [3, 4].
Intestinal disorders such as ulcerative colitis, familiar
adenomatosis, and colonic adenoma are well known as risk
factors for colon cancer [5]. During recent years evidence
has arisen that more than 70% of colorectal carcinomas
develop from adenomatous polyps in a stepwise progres-
sion, a process which is described by the term adenoma-
carcinoma sequence [5, 6]. In postmortem studies an
incidence of adenoma between 30% and 60% in Western
countries was reported [5]. Colonoscopy is the most-
sensitive screening method for colonic polyps and histo-
logical analysis of colonic biopsies is important to confirm
the diagnosis. However, there are miss rates of up to 25%
due to the technique [7]. Many studies have been per-
formed to investigate biomarkers for early detection of
colon cancer and genes like APC, p53, and Ki-ras could be
identified but presently no routine method is available for
distinguishing patients with a high risk for developing
colonic adenoma from those with a low risk [8].
Dig Dis Sci (2008) 53:436–442
Several investigations have shown that the biogenic
amine histamine (2-[4-imidazolyl]ethylamine) and altera-
tions in its metabolism play an important role in pathogen-
esis of colorectal adenoma and carcinoma [9, 10]. Histamine
functions as a neurotransmitter, a mediator responsible for
inflammatory processes, and regulator of hydrochloric acid
secretion from gastric mucosa by stimulation of different
types of histamine receptors [11]. Since histamine was
attributed a mitogenic effect [12] and investigations of the
human colonic mucosa showed increased histamine levels
in patients suffering from colonic adenoma [10], this bio-
genic amine seems to play an important role in the vicinity
of these lesions and might have a function in the regulation
of cell proliferation [13, 14].
In humans, histamine can be catabolized by the two
enzymes diamine oxidase (DAO, EC 1.4.3.6) and histamine
N-methyltransferase (HNMT, EC 2.1.1.8). DAO deaminates
histamine oxidatively forming imidazoleacetaldehyde.
HNMT methylates histamine with S-adenosylmethionine
(SAM) as a cosubstrate, forming Ns-methylhistamine (2-[4-
(N1-methyl)imidazolyl]ethylamine) which is then further
deaminated by monoamine oxidase (MAO, EC 1.4.3.4) or by
DAO [11, 15].
Investigations on the large bowel of rats showed that
only differentiated nonproliferating mucosal cells express
high amounts of DAO whereas in proliferating cells lower
enzyme activities were found [16]. In animal experiments
an increased carcinoma rate in the colon and rectum of rats
after inhibition of DAO was found [16] and evaluation of
DAO in the human colonic mucosa showed decreased
DAO activities in patients with colonic adenoma [10].
These results may possibly indicate an involvement of
DAO in regulation and termination of human colorectal
epithelial cell proliferation and an antiproliferative effect
of this histamine-degrading enzyme. The significance of
HNMT in this context has not been studied yet and was
simultaneously investigated for the first time in this project.
The aim of the study was to analyze the histamine
catabolism in the colonic mucosa of patients suffering
from colonic adenoma. Enzyme activities of DAO and
HNMT were determined in tiny endoscopic biopsies of
patients suffering from colonic adenoma and the results
were compared to the values of healthy controls.
Methods
Patients
Biopsies were obtained from 23 patients in whom diagnosis
of colonic adenoma was confirmed histologically (50%
male, median age 61.5 years, range 23–77 years). Histologic
reports revealed 34 tubular and three tubulovillous adenoma.
437
In the control group six individuals were examined who
underwent colonoscopy due to constipation, rectal bleed-
ing, working-up of anaemia or abdominal pain without any
endoscopic or histologic finding in the lower gastrointes-
tinal tract and without allergic diseases (50% male, median
age 56.5, range 22–74 years, Table 1).
Bad general condition, age younger than 18 or older
than 80 years, diagnosis of celiac disease, inflammatory
bowel disease, gastrointestinal allergy, carcinoma, and
lymphoma were criteria to be excluded from the study.
Since various drugs can inhibit DAO and HNMT, indi-
viduals with a medication with antibiotics, histamine
antagonists, corticosteroids, antidepressants, neuroleptics,
cloroquin, and verapamil were also excluded [17, 18]. This
study complies with the standards of Declaration of Hel-
sinki and current ethical guidelines and was reviewed and
approved by the institutional review board.
Biopsies
About 94 biopsies were obtained endoscopically from the
terminal ileum, different segments of the large bowel such
as from adenoma tissue from patients with colonic ade-
noma, and 26 samples from controls (1–9 mg wet weight,
median 4 mg). They were immediately frozen in liquid
nitrogen and stored at –75C prior to analyses. Each
sample was homogenized for 3 · 10 s in 1 ml 20 mM
bis.tris.Cl pH 7.0 with an Ultra-Turrax T8 using an S8N-
5G probe (Janke und Kunkel, Staufen, Germany) at
20,000 rpm. The buffer contained 1 mM phenylmethan-
sulfonyfluoride (PMSF) as protease inhibitor. Homogen-
ates were centrifuged for 10 min at 23,000g at 4C and
supernatants were used for determination of protein con-
centrations and enzyme activities.
Determination of protein concentrations
Protein concentrations of the homogenates were measured
in duplicate with a commercially available micro-BCA
protein assay reagent kit (Pierce Chemical Company,
Table 1 Study population
Patients with Controls
histologically (healthy
confirmed adenoma individuals)
Number of patients 23 6
Median age 61.5 years 56.5 years
Age (range) 23–77 years 22–74 years
Male/female 11/11 3/3
Number of biopsies 94 26
123
438
Rockford, USA) according to Smith [19]. All procedures
were performed following the instructor’s manual.
Determination of diamine oxidase activities
DAO activities were determined with a radiometric micro
assay based on the conversion of 14C-putrescine (1,4-dia-
mino-[1,4–14C]butane) to c-aminobutyraldehyde which is
spontaneously converted to D1-pyrroline [20]. This com-
pound can be extracted into an organic solvent consisting
of toluene and the radioactivity can be measured by liquid
scintillation counting. The method has been described in
detail earlier [21]. Subsequently the activities of DAO in
homogenates of human colonic biopsies were determined.
In a total volume of 100 ll, a 50 ll sample (H2O as con-
trol) was incubated for 30 min at 37C in 100 mM sodium
phosphate pH 7.0 after starting the reaction by addition of
14
C-putrescine (0.222 Ci/mol; 1 nCi/ll; final 450 lM).
The reaction was stopped by addition of 10 ll perchloric
acid (1% final) followed by alkalization with 50 ll sodium
carbonate pH 12.2 (187.5 mM final), and extraction of
the reaction product D1-pyrroline into 1,600 ll toluene
containing 0.35% 2,5-diphenyloxazole as a scintillator and
determination of the radioactivity by liquid scintillation
counting. Specific enzyme activities were calculated in
international units per milligram protein (U/mg) where 1
unit converts 1 lmol substrate per minute at 37C.
Determination of histamine N-methyltransferase
activities
Measurement of HNMT activity is based on the trans-
methylation from S-adenosyl-L-[methyl-14C]methionine
(14C-SAM) to histamine [22]. The product, radioactively
labelled Ns-methylhistamine, can be extracted at an
alkaline pH into an organic solvent consisting of toluene
and isoamylalcohol. Since the published procedures differ
considerably regarding assay conditions [23–25] the
method was optimized and a reliable assay suitable for
endoscopic samples was established [26]. Analogous to
the DAO assay, a total incubation volume of 100 ll
containing 50 lM histamine as a substrate, 14C-SAM as a
cosubstrate (50 lM, 2 Ci/mol, 1 nCi/ll), 100 mM sodium
phosphate buffer pH 7.5, and 50 ll sample was chosen.
Since both histamine and methylhistamine are potential
substrates for DAO and other soluble copper amine
oxidases present in certain tissues, these enzymes were
inactivated by preincubation with 100 lM aminoguanidine.
The reactions were incubated at 37C for 30 min and
stopped by addition of 60 ll of a solution of 500 mM boric
acid and 1,000 mM sodium hydroxide (final pH 13.9)
causing a pH shift which rendered the extraction step
according to the DAO method described before. The
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Dig Dis Sci (2008) 53:436–442
extraction of 14C-Ns-methylhistamine was performed
with 1,600 ll of toluene/isoamylalcohol (1:1) containing
0.17% PPO as a scintillator. After vortexing each tube for
30 s and centrifugation for 2 min at 10,000g at 25C,
1,400 ll of the organic phase was transferred to a vial and
the radioactivity was determined by liquid scintillation
counting. For HNMT enzymatic activities were also calcu-
lated in international units per milligram of protein (U/mg).
Determination of histamine concentrations
Histamine concentrations were determined in 34 samples
of nine adenoma patients and in 17 biopsies of five
controls using a commercially available radioimmunoassay
according to the manufacturer’s instruction (Beckmann
Coulter, Krefeld, Germany). Concentrations were calcu-
lated in lg histamine/mg protein.
Statistics
Statistical analysis was performed with Graph Pad PrismTM
2.0 using the nonparametric U-test for independent data
(Mann–Whitney–Wilcoxon test). P < 0.05 was criteria for
statistic significance. Results of enzyme activities and
protein concentrations are shown as means ± standard
deviation, wet weights of biopsies as medians.
Results
Protein concentrations
Protein concentrations were determined in homogenates of
all biopsies and calculated in mg protein per ml homoge-
nate. Concentrations ranged between 0.03 mg/ml and
0.60 mg/ml (median 0.21 mg/ml) in biopsies from patients
with adenoma and between 0.08 mg/ml and 0.30 mg/ml
(0.16 mg/ml) in controls. Values were used for calculation
of enzyme activities.
Diamine oxidase activities
Intraassay variation of the radiometric DAO assay was
3.8%; interassay variation was 12.0%. Mean DAO activi-
ties were calculated for adenoma tissue, healthy colonic
mucosa of adenoma patients, and controls and compared to
each other. Activities ranged between 0.04 mU/mg and
1.58 mU/mg protein in the mucosa of patients with ade-
noma and between 0.18 mU/mg and 1.38 mU/mg protein
in controls. Activities were slightly higher in controls
(0.54 ± 0.26 mU/mg protein, mean ± standard deviation)
than in adenoma patients (0.48 ± 0.36 mU/mg protein), but
these results did not reach significance. Activities in
Dig Dis Sci (2008) 53:436–442
Fig. 1 Activities of diamine oxidase in healthy colonic mucosa of
controls and adenoma patients and in histologic-confirmed adenoma
tissue (means ± standard deviation)
adenoma tissues were significantly diminished compared to
those in healthy mucosa in the same patients (0.15 ±
0.07 mU/mg protein versus 0.48 ± 0.36 mU/mg protein,
P < 0.0001, Fig. 1).
Histamine N-methyltransferase activities
Intraassay variation of the radiometric HNMT micro assay
was 4.3%; interassay variation was 16.5%. Activities were
determined in all samples and compared between adenoma
tissue, healthy colonic mucosa of adenoma patients, and
controls. Furthermore, mean activities were calculated for
Fig. 2 Activities of histamine N-methyltransferase in healthy colonic
mucosa of controls and adenoma patients and in histologic confirmed
adenoma tissue (mean ± standard deviation)
Fig. 3 Topographical
distribution of HNMT activities
in the terminal ileum and the
colon in adenoma patients and
in healthy controls
(mean ± standard deviation)
439
left and right hemicolon and for each of the colon segments
ascending, transverse, descending colon, sigmoid and rec-
tum. HNMT activities ranged between 0.01 mU/mg and
1.66 mU/mg protein in biopsies of adenoma patients and
between 0.19 mU/mg and 2.94 mU/mg protein in controls.
In patients with colorectal adenoma HNMT activity was
significantly decreased (0.55 ± 0.38 mU/mg protein,
mean ± standard deviation) compared to controls (1.01 ±
0.61 mU/mg protein, P = 0.0006, Fig. 2). HNMT was also
significantly diminished in adenoma tissue compared to
healthy mucosa in adenoma patients (0.18 ± 0.14 mU/mg
protein versus 0.55 ± 0.38 mU/mg protein, P < 0.0001,
Fig. 2). In addition, HNMT was diminished in terminal
ileum (0.54 ± 0.36 (n = 9) vs. 0.94 ± 0.30 mU/mg
protein (n = 4)), right (0.57 ± 0.39 (n = 17) versus
0.94 ± 0.33 mU/mg protein (n = 9), P = 0.0165) and left
hemicolon (0.55 ± 0.39 (n = 42) versus 1.01 ± 0.71 mU/
mg protein (n = 11), P = 0.0261) in adenoma patients. No
typical topographic distribution of HNMT activities was
found in both groups, but activities were lower in all colon
segments of adenoma patients than in healthy individuals
(Fig. 3).
Linear regression
A significant correlation was found between DAO and
HNMT activities in adenoma tissue (r2 = 0.22, n = 25,
P = 0.0188), in healthy mucosa of adenoma patients (r2 =
0.36, n = 67, P < 0.0001) and in the mucosa of controls (r2
= 0.26, n = 23, P = 0.0127). r2 = 0.40 was calculated for
all investigated biopsies as shown in Fig. 4 (n = 115,
P < 0.0001).
Histamine concentrations
Mean histamine concentrations were higher in homogen-
ates biopsies of adenoma patients (5.5 ± 3.8 lg histamine/
mg protein) compared to healthy individuals (4.3 ± 2.5 lg
histamine/mg protein). These results did not reach
123
440
Fig. 4 Correlation between enzyme activities of DAO and HNMT
(n = 115)
significance. No significant correlation between histamine
concentrations and DAO or HNMT activities were found
(r2 = 0.02 and r2 = 0.03, respectively).
Discussion
The establishment of reliable and sensitive assays for the
determination of the activities of the histamine-degrading
enzymes DAO and HNMT in extremely small human tis-
sue samples is a prerequisite for the application of these
methods in the routine assessment of the histamine
degradation capacity in patients suffering from colonic
adenoma. The assays used in this study give highly
reproducible results, and provide an accurate estimate of
the histamine degradation in human colonic mucosa [21,
26].
In a previous study diminished DAO activities were
reported in patients with colonic adenoma [10]. Topo-
graphical distribution showed a gradient with higher
activities in and close to an adenoma and decreasing
activities with longer distances to the lesion [unpublished
data].
Here for the first time HNMT and DAO activities were
determined simultaneously to evaluate histamine catabo-
lism in the large-bowel mucosa of patients suffering from
colonic adenoma.
In the mucosa of adenoma patients mean DAO activities
were lower than in controls. Furthermore they were sig-
nificantly diminished in adenoma tissue compared to
healthy mucosa.
The obtained HNMT activities in bioptic samples cor-
respond well with the values obtained for human colonic
mucosa in previous studies where larger tissue samples had
been processed [27]. Surprisingly HNMT activities were
significantly diminished in patients with colorectal ade-
noma compared to controls. HNMT was also significantly
diminished in adenoma tissue compared to healthy mucosa
123
Dig Dis Sci (2008) 53:436–442
in adenoma patients. Regarding activities of this enzyme in
different segments of the colon, no topographical distri-
bution was found in either the adenoma group or in the
controls.
DAO and HNMT reached with approximately 0.5 mU/
mg protein similar levels in adenoma patients. Taking into
account that histamine is converted by DAO less efficiently
than putrescine used as a substrate for the assay human
colonic mucosa appears to have a greater capacity to
inactivate histamine by methylation than by direct oxida-
tion. It is important to note that DAO has features of a
secretory protein [28] and may therefore function extra-
cellularily whereas HNMT is a cytosolic protein [29] that
can convert histamine only inside cells.
Elevated histamine levels in the distal segments of the
large bowel of adenoma patients have been reported pre-
viously [10]. In this present study histamine concentrations
were also elevated in adenoma patients compared to con-
trols. These results did not reach significance but the
number of samples was small. Comparing enzyme activi-
ties between adenoma patients and controls substantial
changes in histamine metabolism in these lesions are
obvious. The strong correlation between DAO and HNMT
activities indicates that diminished DAO activities are not
compensated by HNMT and therefore histamine degrada-
tion is completely decreased in such tissues, resulting in
higher histamine concentrations and a prolonged effect of
this biogenic amine. Additionally, in previous experiments,
elevated histamine release from colonic biopsies in ade-
noma patients was described [30, 31]. In our present study
no correlation between histamine concentrations and en-
zyme activities were found, indicating that higher enzyme
activities in controls are not triggered by higher amounts of
histamine. High mucosal histamine concentrations seem
rather to be caused by increased release and decreased
catabolism of this compound.
Since the first genetic polymorphisms on DAO and
HNMT genes in adenoma patients were found evidence has
arisen that alterations in histamine degradation may be
involved in the pathogenesis of these benign tumors [32].
However, large patient populations should be investigated
in the future to evaluate a correlation between enzyme
activities and genetic polymorphisms.
These results will eventually complement the diagnostic
repertoire for colonic adenoma and may lead to new
screening methods. A routine evaluation of the activities of
histamine-catabolizing enzymes DAO and HNMT in
addition to genetic analysis might enable us to detect areas
in the large bowel where adenoma may grow due to a
reduced histamine catabolism, even if there is no macro-
scopic or histological finding. These patients with an
increased risk could be examined periodically by colo-
noscopy in order to enable early detection of new polyps,
Dig Dis Sci (2008) 53:436–442
which could be removed quickly, before the development
of malignancies on the basis of these lesions.
The reported results might also have therapeutic con-
sequences. A prophylactic medication with histamine
inhibitors could have a protective effect since the histamine
type 2 receptor antagonist cimetidine was reported to be
antiproliferative in vitro and in subcutaneous murine tumor
models in vivo [33, 34].
Biogenic amines such as histamine occur in many dif-
ferent foods. High histamine concentrations were measured
in cheese, wine, and sparkling wine, for instance [35].
Strawberries, tomatoes and alcohol are well-known hista-
mine liberators [36]. Risk factors for colorectal cancer such
as meat, alcohol, and nutrition rich in fat may cause
endogenous, non-immunogenic histamine liberation. A diet
free of these histamine-containing and histamine-releasing
nutrients might have a protective effect.
Although in this study only patients with colonic ade-
noma were included, evaluation of histamine-degradation
capacity will also be relevant for patients suffering from
inflammatory bowel diseases including Crohn’s disease,
ulcerative colitis or collagenous colitis, where histamine is
known to play an important role and dysplasia-carcinoma
sequence may occur [37, 38]. Routine analysis of the
activities of DAO and HNMT in addition to the determi-
nation of the histamine content will more precisely reflect
the situation of histamine catabolism in the human colonic
mucosa. This is important to reach a better understanding
of the normal function of this compound and of the
importance of alterations of histamine turnover for the
development and progression of neoplastic and inflamma-
tory intestinal diseases.
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