Histamine Metabolism
GILDON N. BEALL, M.D., Los Angeles. and
PAUL P. VANARSDEL. JR.. M.D., Seattle
THERE IS GENERAL AGREEMENT that histamine is
involved in a number of biological phenomena. For
this reason scientific interest in histamine continues
after more than fifty years of study. This paper is
intended to provide a review of some recent dis-
coveries about the formation, storage and catabo-
lism of histamine.
Histamine is produced by the enzymatic decar-
boxylation of the amino acid histidine. In experi-
mental animals less than 10 per cent of injected
histidine and less than 1 per cent of ingested histi-
dine is converted to tissue histamine. This newly
formed intracellular histamine is released slowly
from the tissues, with a biological half-life of about
50 days.9 Since only a small portion of ingested his,
tidine is converted to histamine, the supply of histi-
dine in the diet has little effect on stores of histamine
in tissues.4
A wide variety of organisms possess the enzyme
histidine decarboxylase which catalyzes this con-
version. Bacterial histidine decarboxylase is respon-
sible for the appearance of histamine in putrefying
organic matter such as the rotted ergot from which
Barger and Dale isolated histamine as the biologi-
cally active material in 1910.1 The concentration of
histamine in animal tissues parallels local concen-
trations of histidine decarboxylase; and the histi-
dine decarboxylase activity can be correlated with
tissue mast cell concentration.5 Histamine formation
by human cells was recently demonstrated by Hart-
man, using basophils from humans with myeloge-
nous leukemia.7
Large species differences have been found in the
histamine content of mammalian tissues. Some ani-
mals, like the dog, have most of their histamine in
mast cells in the connective tissue capsules of vis-
ceral organs. Others, like the rat, have most of their
histamine in the mast cells of skin and subcutaneous
tissues. The rabbit is unique in that relatively large
amounts of histamine are found in the platelets.
Thus, generalizations from experimental animal
studies must be made with caution.
From the Department of Medicine, University of California School
of Medicine, Los Angeles 24 (Beall), and the Department of Medi-
cine, University of Washington School of Medicine, Seattle (Van-
Arsdel) .
The work here reported was supported in part by Grant No. E-15 10
of the National Institute of Allergy and Infectious Disease.
Presented before the Section on Allergy at the 90th Annual Session
of the California Medical Association, Los Angeles, April 30 to May
3. 1961.
VOL. 95. NO. 4 * OCTOBER 1961
* Some recent discoveries about the formation,
storage and catabolism of histamine are re-
viewed. Histamine is formed by decarboxylation
of histidine and stored principally in the mast
cells of connective tissue. Human lung and fa-
cial skin are particularly rich in histamine.
When histamine is injected intravenously, sim-
ulating spontaneous release, it is rapidly metab-
olized and excreted.
The cellular histamine is found within the mast
cell granules with a concentration of about 25 /%jugm
per cell in ox liver capsule.8 Rat mast cells contain
an average of 32 /u/cgm per cell.3 Most human mast
cells are in connective tissues, the number varying
from 20 to 120 cells per five high power fields.
Chronic inflammation increases and acute inflamma-
tion decreases the number of mast cells seen.
Graham and coworkers6 carefully measured the
distribution of histamine among the various formed
elements of human blood. By far the greatest concen-
tration (1 jtq-gm per cell) was found in basophils,
much lower than that of tissue mast cells. The high
blood histamine levels observed in chronic myelo-
cytic leukemia have been correlated with a high baso-
phil content.12 Data on other human tissues are
comparatively sparse. The highest tissue concentra-
tions are found in facial skin (30.4 [tgm per gm),
lung (33 ,.ugm per gm), stomach (14 ,ugm per gm)
and duodenum (14 ,ugm per gm) .
After its intracellular formation (by histidine de-
carboxylase) histamine remains inactive within
mast cell granules even after cellular disruption and
differential ultracentrifugation. Three hypotheses as
to the nature of this intracellular binding have been
presented. Peptide bonds to protein, ionic bonds to
heparin, or binding or adsorption to lecithin may
be involved. Heparin and histamine will form a
precipitate in vitro which resembles the mast cell
granules. Conversely, lecithinase activation seems
to be instrumental in producing histamine release.
At present, the mode of binding remains unknown.
The degradation of endogenous histamine follow-
ing its release from cellular stores has not been
directly studied due to the technical difficulties
involved. Instead, most studies have involved the
intravenous or subcutaneous injection of trace
amounts of histamine. Isotopic labeling of hista-
mine has aided the identification of metabolites.
237
 CH2CH2
HN
N
HISTAMINE
CH22COOH
HN N CH3N
IMIDAZOLE ACETIC ACID i,4-METHYLHISTAMINE
(ImAA)
[.nCH2COOH
CH3N
ImAA RIBOSIDE N- 00
1,4-METHYL ImAA
Figure 1. Pathways of histamine catabolism.
Injected radioactive histamine is rapidly cleared
from the plasma and the metabolic products are
rapidly excreted in the urine.2 There is no ap-
preciable ring-splitting or respiratory excretion
of radioactive carbon dioxide after injection. When
small amounts are injected, very little unchanged
histamine appears in the urine. We gave 100 ,tgm
of radioactive histamine intravenously to humans
and found that the plasma was cleared of radio-
activity in a few minutes; 70 per cent or more of
the administered radioactivity had been excreted
into the urine within 24 hours, and all within 48
hours. Less than 5 per cent of this was unchanged
histamine.
There are two main pathways of histamine catab-
olism (Figure 1). First, histamine may be oxidized
to imidazole-4(5) -acetic acid (ImAA) through imi-
dazole-4(5) -acetaldehyde. Much of the resulting
ImAA is then conjugated with ribose, leading to
urinary excretion of both ImAA and ImAA ribo-
side." In the second pathway, histamine is methyl-
ated at the ring imino-nitrogen to form 1,4-
methyl-histamine. This is followed by oxidation of
the side chain, presumably through the correspond-
ing aldehyde to 1,4 methylimidazoleactic acid (me-
ImAA).
There is some species variation in the amounts
of the various radioactive metabolic products that
are excreted following administration of radioactive
histamine. In humans apparently both pathways of
catabolism are used. Schayer10 found most of the
radioactive histamine excreted as me-ImAA by
CH2CH2 healthy young males.10 Our studies with a group of
N
hospital patients and normal males demonstrated
ImAA as the principal metabolite.2 There were no
consistent variations in the amounts of the metabo-
lites found in patients with asthma, "histamine"
headaches or Laennec's cirrhosis.
The catabolism of histamine is thus a process
which proceeds rapidly and completely and there is
N no evidence that it is ever altered significantly in
vivo in man. Histamine metabolizing enzymes re-
main surprisingly active even in extensive paren-
chymatous diseases.
Department of Medicine, UCLA Medical Center, Los Angeles 24
(Beall).
REFERENCES
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238 .CALIFORNIA MEDICINE