Effects of Oral Histamine, Histidine and Diet on Urinary
Excretion of Histamine, Methylhistamine and
1-Methyl-4-imidazoleacetic Acid in Man
G. GRANERUS
Department of Clinical Physiology, University of Goteborg and
Department of Clinical Physiology, University of Lund, Sweden
Abstract: Granerus, G. Effects of Oral Histamine, Histidine and Diet on Urinary Excretion of
Histamine, Methylhistamine and 1-Methyl-4-imidazoleaceticAcid in Man. Scand. J . din. Lab.
Invest. 22, Suppl. 104, 49-58,
1968. The urinary excretion of 1-methyl-4-imidazoleaceticacid
(1,4-MeImAA) was measured in eight healthy subjects. In some experiments the excretion of
histamine and methylhistamine was determined simultaneously. Large amounts of histamine by
mouth increased the urinary excretion of l,rl-MeImAA, whereas there were no certain effects of
histidine or 3-methylhistidine. There were indications that dietary factors other than the histamine content of the food may be of importance for the large variations in the urinary excretion of 1,4-MeImAA sometimes seen in subjects given a mixed diet. A high protein intake,
sometimes, but not consistently, increased the urinary excretion of 1,4-MeImAA. Other possibly
important factors discussed are the absorption of histamine from the intestine and the role played
by the intestinal bacterial flora. It is suggested that investigations of histamine me:abolism in
man may have to be performed under standardized dietary conditions.
Key-words: Diet; histamine metabolism in man; histidine.
Due to the work of Schayer (22) we know 14C-1,4-MeImAA is excreted in the urine
that quantitatively the most important meta- in amounts which are 25-50 times larger
bolite of histamine in man is l-methyl-4- than those of 14C-histamine (16). Since the
imidazoleacetic acid (1,4-MeImAA).Recent- urinary excretion of endogenous histamine
ly the normal urinary excretion of 1,4- is of the order of 10-30 pg per day (16,
MeImAA has been established independent- 24) it was assumed that the excretion of
ly by two different methods. Granerus and endogenous 1,4-MeImAA would be about
Magnusson (11) found that the excretion va- 1 mg per day. Thus the values obtained are
ried between 0.9 and 3.0 mg per 24 hours of expected magnitude but occasionally
in eleven healthy subjects but in two healthy much higher values have been found. The
males 8-9
mg/24 hours were excreted. present study was undertaken to elucidate
Tham (28) studied 34 healthy individuals, some factors which might increase the exaged 19 to 65 years. The mean urinary ex- cretion of 1,4-MeImAA in normal human
cretion of 1,4-MeImAA was 2.65 mg/ 24 beings.
The urinary excretion of free histamine
hours (0.76-4.49 mg/24 hrs). No significant
difference between men and women was in normal adults appears to vary only little
in different materials (16). Mitchell and
observed.
After injection of 14C-histamine in man Code (18) found that fasting lowered and
49
meat diet increased the urinary histamine.
Irvine, Duthie & Waton (14) confirmed
these observations and also found that the
increase in urinary histamine after a meal
of meat was similar to that after a corresponding amount of free 1-histidine by
mouth. The urinary histamine peak after
meat or 1-histidine disappeared during treatment with succinylsulfathiazoleand Irvine et
al. concluded that intestinal bacteria can
contribute to the urinary histamine by decarboxylating histidine in the food. Increased urine histamine after 1-histidine per 0s
have later been reported (20,25). DunCr,
Liljedahl & Pernow (6) could not detect any
increase in urinary histamine after histidine
orally but they showed that the urinary output of 4(5)-imidazoleacetic acid, another
histamine metabolite, increased markedly.
In animals imidazoleacetic acid is formed in
large amounts from histidine by a route not
involving histamine (22). Therefore, this metabolite may not be a relieable measure of
histamine metabolism in man.
Large amounts of histamine have been
given by mouth to human subjects without
significant increase in urinary free histamine
(1, 18, 26). In dogs a small and shortlasting
increase was found after enteral administration of histamine (13, 17). 14C-histamine
given by the mouth to human subjects resulted in no detectable excretion of unchanged
14C-histamine (3, 21) and, according to
Schayer (21), the main radioactive metabolite in the urine was 1,4-MeImAA.
This raised the question if the intake of
histamine and histidine by mouth can influence excretion of 1,4-MeImAA in the
urine. Histamine may be present in the
food or may be synthesized from histidine
in the lumen of the alimentary tract. Such
"exogenous" histamine could be absorbed
from the gut and partly excreted in the
urine as 1,4-MeImAA. An uncontrolled ingestion or intestinal synthesis of histamine
would thus greatly limit the value of 1,4MeImAA-determination in the urine when
50
information on "endogenous" histamine
metabolism is sought.
The possibility was also considered that
urinary 1,4-MeIrnAA is derived from the
catabolism of some other substance than
histamine or methylhistamine. There is so
far no experimental data for the existence
of such a substance. Theoretically, 3-methylhistidine might be degraded by the same type
of reaction as that transforming histidine
into imidazoleacetic acid and then contribute to the urinary 1,4-MeImAA. 3-Methylhistidine is not found in the food but is
normally occuring in the human urine (4).
MATERIAL AND METHODS
Eight healthy subjects were studied (Table
I). Three of the subjects were given histamine dihydrochloride (Merck) by mouth
after breakfast. Subject A had it dissolved
in 100 ml of water and took it in small
draughts during a couple of hours. Subjects
B and C had the dose divided in three parts
which were taken with about three hours
interval. Every portion was taken in a glass
of water and the mouth was rinsed with two
glasses of water afterwards. The same
scheme was followed next time histamine
loading was performed in these two subjects.
Urine was collected during 24 hours from
the beginning of histamine intake. Otherwise
urine was always collected from 8 a.m. in
intervals of 24 hours. The urine bottles
contained 10 ml of concentrated hydrochloric
acid and where kept cold.
To three of the five histamine doses given
were added a small amount of histamine
labelled in the 2 position of the imidazole
ring (The Radiochemical Centre, Amersham,
England). The specific activity was such
that the administered amount contained 12 pCi, Histamine doses, labelled and nonlabelled, are given in Table II.
L-histidine monohydrochloride (Roche)
was given by mouth to four subjects. The
dose of 5 g was divided in three portions
Table I. Subjects studied
Subject
Sex
Age
years
Height
cm
Weight
kg
A
B
C
D
E
F
G
H
M
M
F
F
M
F
M
F
27
38
31
24
21
28
28
28
178
190
168
163
184
155
176
174
62
90
72
62
67
50
65
60
of 1 g, 2 g and 2 g, which were taken one
hour apart starting at 8.30 a.m. after breakfast. However, subject F had later one day
1 g at 4 p.m. and the next day 5 g undivided
at 9 a.m. Histidine was usually taken in a
glass of orange juice.
Subject F took L-3-methylhistidine (Calbiochem) dissolved in water per 0s twice,
both times after breakfast at 9.30.
In the histamine and histidine loading
experiments the diet was "mixed". This
meant some sort of meat, including minced
meat or fish every day, bread and butter,
milk and cheese, rice or potatoes or other
vegetables and tea, coffee or fruit juice to
drink. It was the ordinary diet of the subject
and not rigorously fixed. Subject A had
identical diets on days 1 and 8. The dietary
experiments comprised three types of diets:
One with a low protein content, 5-20 g
per day, mainly consisting of vegetables and
fruits but some bread, butter and milk were
allowed, one "mixed" diet, as described
above, and one high protein diet with
about 100 g of protein per day, which usually meant two beef meals a day and ample
supply of milk and cheese. The caloric intake with the low protein diet was about
50 yo of that with the high protein diet.
Subject B and subject C in their first experiments made an exception by nearly fasting
when on the low protein diet. Subject F was
on a low protein diet when she had histidine
per os, but during the five days around the
ingestion of 3-methylhistidine there was a
constant intake of 85 g of beef per day. No
diets were analyzed for their histamine content.
Histamine in urine. Urinary histamine was
determined by bio-assay1 on the isolated guinea-pig ileum after absorption of histamine
to a strongly acid cation exchange resin (30).
Methylhistamine in urine. The method for
determination of methylhistamine (l-methyl4-(/?-aminoethyl)imidazole) in tissues (31)
was modified to suit human urine samples.
The method included a spectrophotometric
quantitation of the methylhistamine complex
with 2,4-dinitrofluorobenene (DWB)2(12).
I-Methyl-4-imidazoleaceticacid in urine.
The method is describe1 by Granerus et al.
(11). Some minor modifications were introduced to get the various steps of the method
more standardized and easier to handle (10).
Analysis of 14C-labelled compounds in
urine. The methods used have been developed by Schayer and described by e.g. Nilsson, Lindell, Schayer & Westling (19) and
Lindell, Nilsson, Roos & Westling (15). The
following substances were determined: Histamine, methylhistamine (l-methyl-4-(8aminoethyl)imidazole), 1,4-MeImAA (1methyl-4-imidazoleacetic acid) and ImAA
(4(5)-imidazoleacetic acid).
The excretion of total 14C-activity in the
urine was measured as described by Schayer
& Cooper (23).
RESULTS AND COMMENTS
Effectso f histamine by mouth
The excretion of histamine, methylhistamine and 1,4-MeImAA in the urine these
days and during some control days before
1)
2,
Kindly performed by Dr. H. Wetterqvist, Lund
The analyses were kindly performed by Dr. T.
White, Lund
51
Table 11. Urinary excretion of histamine (Hi), methylhistamine (MeHi) and I,4-MelmAA (@24 hrs)
and corresponding urinary 14C-labelled compounds and total 14C (expressed as per cent o f given dose)
before, during and after histamine loading per os
Subject A: 67.5 mg histamine base f 8.5 pg 1%-histamine on day 8.
Day
Hi
MeHi I,4-MeImAA
I4C-Hi
1
37
170
92
210
400
190
8
9
2500
22600
2400
I4C-MeHi
14C-1,4-MeImAA
To~.'~C
-
-
0.6
0
0.3
0.1
21.3
0.9
49
5
Subject B: 24.0 mg histamine base on day 2.
,, - 16.6 pg I4C-histamine on day 21.
+
~
1
2
6
7
21
22
48
55
27
43
71
50
200
310
240
190
530
300
3400
9400
3000
5000
12300
7100
0
-
~~~~
-
-
-
-
-
-
-
13.6
0
27
3
-
-
-
-
-
0
11.8
0
0
-
Subject C: 16.0 mg histamine base on day 2.
1 1.O p g i4C-histamine on day 21.
,,
-+
1
2
3
7
8
21
22
33
31
29
56
58
78
77
170
150
100
130
150
260
180
3400
6300
3600
3500
3800
3900
2400
0.4
-
and after the histamine intake are shown
in Table 11. Information is also given on
total 14C-activity and 14C-labelled compounds in the urine when 14C-histamine
was given. In subject A 14C-ImAA (total)
was also measured, day 8 it was 1.6 yo,day
9 none. Only about 50% or less of the histamine given by mouth could be accounted
for in the urine as measured from total 14Cactivity excreted during 48 hours. The histamine metabolite, 14C-1,4-MeImAA, constituted 43%, 50% and 33% respectively
of the total urinary 14C-activity during the
24 hours following histamine loading.
52
-
-
-
-
36
6
A conspicuous increase in non-radioactive
1,4-MeImAA was found in subject A who
received the largest oral dose of histamine.
Subject B and C who had smaller doses of
histamine also showed some increase, but
the changes were more difficult to evaluate
because of fluctuations during control days.
Slight increments were also noted for histamine and methylhistamine.
The urinary 14C-labelled histamine and
methylhistamine were always less than one
per cent of the given dose. The value of
14C-histamine might even be falsely high
because the urine contained some conjuga-
ted 14C-histamine which in the analytical the major part appearing as L4-MeImAA.
The subjects did not get any subjective
procedure of Schayer would be partly hydrolyzed to 14C-histamine (Granerus unpubli- or objective symptoms which might have
shed). The very low vaIues of 14C-methyI- been caused by histamine.
histamine in the urine imply that the urinary
ratio of 14C-1,4-MeImAA/14C-methylhista- Effects of histidine by mouth
mine is higher when histamine is taken by
All subjects complained of headache about
mouth than when it is injected (12). The an hour after the last histidine intake and
same is true for the ratio of the non-radio- subject D also developed flushing over the
active compounds.
chest and in the face. The excretion of histaThe addition of a tracer dose of 14C- mine, methylhistamine and 1,4-MeImAA in
histamine, to the large dose of histamine
the urine are shown in Table 111. There is
given by the mouth, makes it possible to no pronounced and consistent effect on the
calculate that about one third to one half excretion of histamine metabolites in these
of the ingested histamine reaches the urine, subjects. In subject D, however, the highest
histamine and methylhistamine values appeared on the day of histidine loading wheTable 111. Urinary excretion of histamine (Hi), reas the urinary excretion of 1,4-MeImAA
methylhistamine (MeHi) and 1,l-MelmAA (pg/24 was not significantly increased. In B and C
the maximal excretion of methylhistamine
hrs) after histidine per 0s
occurred on the second and third day respecSubject B: 5 g histidine. HCl on day 2.
tively after histidine intake. In these subjects
urine histamine was not much affected.
Day
Hi
MeHi
1,4-MeImAA
Histidine was also given to subject F when
she had a low protein diet (see below).
1
53
230
5900
2
3
4
48
42
62
280
320
310
5900
6800
6100
Subject C: 5 g histidine. HCl on day 4.
1
2
3
4
5
6
7
32
33
29
47
35
-
85
72
89
120
160
220
130
4000
3500
3500
4100
3200
3800
7800
Subject D: 5 g histidine. HC1 on day 2.
1
2
3
4
5
6
48
110
43
97
78
79
240
310
170
210
150
190
3700
3400
5200
6800
3700
4500
Effects of dietary variations
One of the healthy men (E) reported to
excrete, occasionally, 8-9 mg L4-MeImAA
per day in a previous investigation (11) was
followed during six consecutive days while
on a mixed diet. There was a great variability in the daily excretion of 1,4-MeImAA;
with values ranging from 2.1 to 33.2 mg
per day, the later being the highest value
recorded in a normal person. There were
no symptoms of illness. Subjects E and A
were therefore studied with controlled diets;
first three days with low protein diet and
then three days with a high meat content
in the diet. On the first day of high protein
intake there was a considerable increase in
urinary 1,4-MeImAA, which gradually decreased the following two days (Fig. 1 top).
Similar experiments were made with subjects
B and C without much change in urinary
53
m g / 2 4 hrs
30A
E
20--
lo--
0-
r
B
C
C
1 : : : : : : : : : : ;
-
! ! : ! : : q
days
Fig. 1. Urinary 1,ll-MeImAA in subjects A, B, C
and E while on low =I
and high
protein diets.
1,4-MeImAA when diet was changed (Fig.
1 middle). About six months later these experiments were repeated in subjects A and
C. This time there was no or only a small
increase in 1,4-MeImAA excretion when diet
was changed, but in subject A there was an
unexpected increase on the fourth day after
the change (Fig. 1 bottom).
In subjects A and F this diet regimen
54
was inserted between two weeks of mixed
diet to evaluate the spontaneous variations
in urinary 1,4-MeImAA excretion compared
with those possibly induced by the diet.
Subject A, on the mixed diet showed considerable variations which diminished with
low protein diet, while subject F had a
rather stable excretion, with only a small
increase with high protein diet (Fig. 2).
Two other subjects (G and H, Table Iv)
have been investigated in a similar manner,
both eating almost identical diets. Subject
H increased substantially in urinary 1,4MeImAA on the second day of high protein diet, whereas subject G did not show
such an increase. Both had rather high exretion of 1,4-MeImAA on day 1 and 2 on
mixed diet. Urinary histamine and methylhistamine varied in parallel with the increases and decreases in 1,4-MeImAA. As in
the histamine loading experiments the high
values of urinary 1,4-MeImAA caused a
high 1,4-MeImAA/methylhistamineratio.
In subject F histidine was given orally for
two days instead of high protein meals. The
histidine was given after a period of three
days with low protein intake. The histidhe
did not increase 1,4-MeImAA in the urine
(Fig. 2) but there were symptoms of nausea
and headache. The last day meat was given.
About an hour after dinner she had malaise
and vertigo and the urinary 1.4-MeImAA
was slightly increased.
Ingestion of 3-methylhistidine
3-Methylhistidine, 42 and 100 mg, was
given by mouth, on day three in each of
two periods of five days of continuous measurements of urinary excretion of 1,4MeImAA (Fig. 2). Ingestion of 3-methylhistidine did not increase the excretion of
1,4-MeImAA. No untoward effects of the
3-methylhistidine were noted. Simultaneous
measurements of urinary methylhistamine
gave the following results during the two
periods: 45, 80, 75, 95 and 55 respectively
110, 100, 130, 110 and 140 pg/24 hrs.
Table Iv. Urinary excretion (pug124 hrs) of histamine (Hi), methylhistamine (MeHi) and 1,l-MeImAA
in two subjects with varying diets
Day
Hi
Diet
Mixed
Mixed
Low
Low
Low
High
High
High
120
210
24
13
14
42
37
MeHi
180
280
130
95
130
280
340
-
410
580
200
110
130
-
130
330
1,4-MeImAA
410
550
140
160
140
240
410
-
10100
11000
2800
2100
2500
-
2000
4200
10000
12000
2500
3400
3200
7400
18600
-
Subject G (left column) and subject H (right column): "Mixed", "low" and "high" refer to mixed
diet, low and high protein diet, respectively.
different foods revealed that especially cheeThe results show that there is a great va- se and other foodstuffs contaminated with
riability in the daily excretion of 1,4- bacteria sometimes contained rather large
MeImAA in the healthy subjects investiga- amounts of histamine (Wetterqvist pers.
ted. When the diet was of the low protein corn.), though not enough to explain the
type rather low amounts of 1A-MeImAA most striking increases in urinary 1,4were always found in the urine. On the other MeImAA, particularly since only one fourth
hand, ingestion of a high protein meal on or less of ingested histamine will appear in
some occasions resulted in a substantial the urine as 1,4-MeImAA. Furthermore, the
increase of urinary 1,4-MeImAA. Conse- high protein diet only increased the urinary
quently it is possible that the occasional 1,4-MeImAA in some persons on some
high values of urinary 1,4 MeImAA were in occasions; histamine present in the food
some way related to the protein intake. The would have caused a reproducible increase.
subjects in which urinary 1,4-MeImAA However, large variations in histamine conchanged with the protein content of the diet tent of the food, due to varying protein
decay cannot be excluded.
also tend to show a "spontaneous" variabilIt appears likely that formation of histaity in the excretion of 1,4-MeImAA when
mine
in the gastrointestinal tract should be
on a mixed diet.
dependent on the presence of histidine in
The most constant finding was that hista- the food. The amounts of histidine in the
mine taken by mouth increased the 1,4- diets are roughly proportional to the protein
MeImAA in the urine. Therefore the varia- content because the histidine fraction of the
tions in the normal subjects of the present different proteins vary only about two or
experiments could depend on variations in three per cent (29). On a mixed diet the
intestinal absorption of exogenous histami- daily intake of histidine is therfore rather
ne, either present as such in the food or constant. Yet two of the subjects examined
formed in the gastrointestinal tract.
had highly varying amounts of 1,4-MeImAA
The histamine content of the diets used in the urine with the mixed diet. A high
was not known at first. Later analysis of protein diet only occasionally increased uriDISCUSSION
4 hrs
A
F
1°T
F
1°T
. . . . . . . . . . . . . . . . . . . . . . . .
days
Fig. 2. Urinary 1,4-MeImAA in subjects A and F
with different diets: I/////\ ”mixed”, I
1
low and
high protein diets.
1- 1 g and El 5 g histidine-HC1 per 0s.
42 mg and 1- 100 mg 3-methylhistidine per 0s.
=
nary 1,4-MeImAA and addition of one to
five grams of histidine by mouth did not
alter the urinary excretion of 1.4-MeImAA
in these experiments. Therefore some other
factor than the histidine or protein content
of the diet would seem to be of importance.
Little is known about the absorption of
histamine from the human gut. When histamine was taken by mouth not more than
54% was a‘bsorbed during two days as
measured from total urinary radioactivity.
Schayer (21) fed a man 0,l mg 14C-histamine and the found 66% of the total activity
56
in the urine in 48 hours. Beall (3) made the
same experiment and got 75% in the urine
in 48 hours. Recently Sjaastad (26) observed
that the fecal excretion of free histaminelike activity varied between 0.5 and 11%
of an oral histamine dose and tended to
increase with increasing doses. He also found
that histamine administered to various segments of the human gut did not add to the
excretion of histamine in the urine. These
findings indicate that histamine is incompIetely absorbed, particularly in the distal part
of the gut. It is interesting to note that Mitchell et al. (18) observed that ingestion of
histamine together with a meal of bread,
milk and butter increased the output of
histamine in the urine, but when either was
taken separately no increase occurred. They
suggest that the absorption of histamine
from the gut is increased ,inthe presence of
the meal. Then, besides containing some
histamine, the diet may influence the absorption of exogenous histamine. Such a
mechanism may explain some variations in
the excretion of 1,4-MeImAA if the diet is
not absolutely fixed.
Many proteolytic bacteria of the human
intestine are able to decarboxylate histidine
in vitro (2, 7, 8, 9). These proteolytic bacteria are favoured by a diet rich in animal
protein and inhibited by a diet which favours
the growth of the acidophilic group of bacteria, i.e. vegetables, grain foods, lactose and
dextrin (27). The diets used here may have
distupbed the balance between these two
principal groups of bacteria in susceptible
individuals and induced a ”spontaneous”
synthesis of histamine followed by an
increased excretion of 1,4-MeImAA in the
urine. To avoid this a standard diet was
developed (10). On this the urinary excretion
of 1,4-MeImAAin normal individuals varied
very little. It thus seems likely that some
sort of ”basal dietary conditions” are necessary for investigations on histamine mebboIism in man.
3-methylhistidine given by mouth did not
affect the excretion of MeHi or 1,4MeImAA in one subject. It might be argued
that the amounts given were rather small,
particularly in relation to the amounts of
histidine given. However, 3-methylhistidine
differs from histidine in being quite inert
metabolically. Thus, 50-90%
are found
in the urine in unchanged form after injection
of 3-14CH3-histidine into the chick, rabbit
and rat (5). The meat intake was kept constant during the periods of urine collection
because the urinary excretion of 3-methylhistidine seems to be influenced by altering
the type or amount of meat protein (4). The
total intake of protein (about 50 g) might
correspond to an excretion of about 50 mg
3-methylhistidine in the urine per day (4).
The amount of 3-methylhistidine given by
mouth thus equals and doubles what is calculated to be present in the urine. If orally
administered 3-methylhistidine is absorbed
and not incorporated in the tissues the results imply that there is no significant conversion of 3-methylhistidine to urinary 1,4MeImAA in the body, neither by decarboxylation nor oxidative deamination.
ACKNOWLEDGEMENTS
Miss M.-B. Johansson and Mrs. S.-B. Ekman are thanked for their skilful technical
assistance. Financial support was obtained
through U.S. Public Health Service grant
No. 5-RO1-A1 03379 and the Faculty of
Medicine, University of Goteborg.
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