Biologically Active Amines Found in Man. Their Biochemistry, Pharmacology, and Pathophysiological Importance

248 Pages·1969·25.43 MB·English

by  Franz Franzen and Kurt Eysell (Auth.)

BIOLOGICALLY ACTIVE
AMINES FOUND
IN MAN
Their Biochemistry, Pharmacology, and
Pathophysiological Importance
by
FRANZ FRANZEN
and
KURT EYSELL
PERGAMON PRESS
OXFORD · LONDON · EDINBURGH · NEW YORK
TORONTO · SYDNEY · PARIS · BRAUNSCHWEIG
Pergamon Press Ltd., Headington Hill Hall, Oxford
4 & 5 Fitzroy Square, London W.l
Pergamon Press (Scotland) Ltd., 2 & 3 Teviot Place, Edinburgh 1
Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, New York 10523
Pergamon of Canada Ltd., 207 Queen's Quay West, Toronto 1
Pergamon Press (Aust.) Pty. Ltd., 19a Boundary Street,
Rushcutters Bay, N.S.W. 2011, Australia
Pergamon Press S.A.R.L., 24 rue des Écoles, Paris 5e
Vieweg & Sohn GmbH, Burgplatz 1, Braunschweig
Copyright © 1969
F. Franzen and K. Eysell
AU Rights Reserved. No part of this publication may be
reproduced, stored in a retrieval system, or transmitted, in
any form or by any means, electronic, mechanical, photo­
copying, recording or otherwise, without the prior permission
of Pergamon Press Limited.
First edition 1969
Library of Congress Catalog Card No. 75-78590
Printed in Great Britain by Alden & Mowbray Ltd, Oxford
08 013877 2
PREFACE
THE biologically active amines indigenous to the body are currently of great
interest to research workers in the fields of biochemistry, pharmacology, and
clinical medicine.
Since the last extensive survey of the entire field of "biogenic amines" by
M. Guggenheim (1951), there has been a considerable increase in our know­
ledge of these compounds. Research, which was largely confined to plants
and animals, has led to a recognition of their importance in man and has
stimulated research in the clinical field.
This book is addressed both to clinically and scientifically orientated
readers. It attempts a brief summary of the present knowledge of the bio­
chemistry, pharmacology, and the pathophysiology of biologically active
amines, which have so far been found in man.
Cologne F.F.
K.E.
VII
CHAPTER 1
DEFINITIONS AND THEMATIC DELINEATION
ACCORDING to Guggenheim(1) "biogenic amines" are "organic bases of low
molecular weight, which arise in consequence of metabolic processes in
animals, plants, and micro-organisms. They comprise aliphatic, alicyclic,
and simple heterocyclic compounds and appear in the cellular metabolism
as basic elements, intermediary or catabolic products of varied physiological
importance."
As the parent substance of animal bases, protein calls for almost exclusive
consideration.(2) The biologically active amines of man might be looked
upon as derivatives of protein. In a narrower sense they are bases, which
arise through decarboxylation of α-amino-acids. This clearly distinguishes
them from protein derivatives whose biosynthesis takes place in a different
manner, as in the production of betaine, the methylation of amines, the
conversion of amino-acids and amines to amides by hydrolysis or other
processes.
How far this differentiation of biologically active amines—adopted for
systematic reasons—will also correspond to the progressive explanation of
their biochemical nature, remains an open question. For example, recent
investigations*3* 4) in the mammal have made likely the production of dop-
amine by the hydroxylation of tyramine; thus dopamine, according to our
definition, could not be differentiated.
This book is concerned with the amines derived by decarboxylation of
oi-amino-acids in human beings and with some of their especially interesting
metabolites.
A* 1
CHAPTER 2
BIOCHEMISTRY
I. ORIGIN OF BIOLOGICALLY ACTIVE AMINES
1. General remarks
Biologically active amines are produced in man and in animals by bacteria
(5-39) j by tissue(39~103' 115) metabolism. The enzymes which catalyse
an(
this process (amino-acid decarboxylases) have pyridoxal-5-phosphate(1'35'
37, 38, 68, 69, 74, 87, 91, 93, 94, 105-9, 1835) OenZyme. The
as thdr common C
questions of stereo- and substrate-specificity of amino-acid decarboxylases
are referred to in the appropriate enzymological literature/35, 38'61'110)
The animal decarboxylases differ from the bacterial ones in having a lower
quotient of activity(1, 61» 110) and a pH optimum in the alkaline instead of
the acid region/1' 9,12-14,24-27,31,35,37,45,103,108,111) .
Aminoacid
decarboxylases are found in a variety of animal organs, such as the kidney,
liver, intestine, stomach, pancreas, spleen, lymphatic nodes, uterus, lung,
heart, skeletal muscle, blood vessels, the adrenal medulla, sympathetic nerves
and ganglia, spinal cord, brain, bone marrow, etc. The carboxylases differ
in activity depending on the species and/or the organ from which they were
derived and upon the nature of the substrate used. In human beings, amino-
acid decarboxylases have been discovered in the kidney/53-56* 61* 75,103, 154*
1455) the liver/75' 154' 1455) the spleen/1455' 1832) the mucosa of the stomach,
(80, 1455) (55,103,112) (153, 154, 1455)
theintestine thelung) the adrenal meduUaj
(103) the brain/97'113) the skin/1455) the bone marrow/1455) and the basophil
leucocytes/1454) Very high decarboxylase activity has been found in car-
cinoids of the intestine, in their métastases/75' 76* 87* 103' 112' 114~16> and in
phaeochromocytomas/87'103'114'115'117,118) Histidine decarboxylase occurs
in foci and unaffected parts of the skin of urticaria pigmentosa patients/119*
635, 636, 677) jj j tj f the cardia and fundus of a patient with a
as we as n ssue 0
cardiac carcinoma;(1835) high histidine decarboxylase activity was also
found in homogenates of the spleen in cases of a mastocyte system
disease.(1832) The presence of amino-acid decarboxylases in the human may
be inferred from investigations in which the parenteral injection of (mostly
isotope-marked) amino-acids caused an increased production of the corres­
ponding amine/60' 63' 81' 118· 120· 121)
2
BIOCHEMISTRY 3
2. Specific observations
Decarboxylase activity and the amine content of an organ by no means
always run parallel. For example, in rats, guinea-pigs, and rabbits/71} the
kidney and the liver are rich in 5-hydroxytryptophane-decarboxylase, but they
contain little 5-hydroxytryptamine; the situation is reversed in the spleen
of the same animals. It may be that the high amineoxidase activity of the
kidney and the liver, and the abundance of thrombocytes in the spleen account
for these findings. Nevertheless, the figures for decarboxylase activity and
amine content(34) of different cerebral regions cannot be accounted for in
the same manner. As can be seen from Table 1(134) the hypothalamus with
moderate* decarboxylase activity and a considerable monoaminoxidase
activity has a high serotonin content. So far only a limited number of esti­
mates of decarboxylase activity have been made in human tissues, but they
may be compared with the amine content of the same organ in health and
disease in the small intestine, colon, appendix, liver, spleen, and skin (Table 2).
Decarboxylation of amino-acids under normal circumstances—e.g. of
tyrosine, tryptophane, histidine—represents a very small part of their meta­
bolism. Thus the endogenous serotonin production in man may be estimated
at 10-20 mg per 24 hr(137>138) compared with a daily intake of 500-1000
mg tryptophane in the food. This represents the decarboxylation of only
1-2% of the amino-acid for the formation of amines/137-9) A similar rate
of production is assumed for tryptamine, which also originates from trypto-
phane.(89) Changes which arise in pathological conditions will be considered
in the section concerning amine-metabolism and when discussing the amine-
producing tumors.
Little is known about factors which limit the production of amines. The
metabolic reaction which limits the biosynthesis of dopamine and serotonin
is believed not to be the decarboxylation of their biochemical precursors
dopa and 5-hydroxytryptophane by the ubiquitous decarboxylase, but to be
the hydroxylation of the parent compounds tyrosine, and tryptophane/77' 82*
140-3,189) under comparable experimental conditions the production of
serotonin from 5-hydroxytryptophane(71' 140) took place 30-40 times faster
than from tryptophane/141* and the production of dopamine and noradren-
aline respectively from labelled dopa was 70-100 times faster than from
labelled tyrosine.(190) In the biosynthesis of noradrenaline, the hydroxylation
of dopamine, catalysed by dopamine-/?-oxidase, takes place fairly slowly and
is considered to be a rate-limiting reaction/726, 749)
The difficulty of proving the existence of the precursors of dopamine and
serotonin biosynthesis in tissues, i.e. dopa and 5-hydroxytryptophane, is
probably connected with the fact that both are produced only in small
* The decarboxylase activity shown in Table 1 was determined using dopa as the sub­
strate; when 5-hydroxytryptophane is used as the substrate the enzyme activity is less.
TABLE 1. LOCALIZATION OF ENZYMES AND ENDOGENOUS AMINES IN THE BRAIN
(by J. W. Daly and B. Witkop,(134) slightly modified)
Cerebral region: Cerebrum Corpus Caudate Hypo­ Thalamus Mid-brain Pons Medulla Cerebellum
callosum nucleus thalamus
O
AMINES*<96· 122' 124 9> o
Dopamine trace trace + + + + + + + + trace trace trace
O
Noradrenaline trace trace + + + + + + + + + + + + trace
o
Serotonin trace trace + + + + + + + + + + + trace trace >
Histamine trace trace + + + + trace trace trace r
r
Acetylcholine + + + + + + + + + + + + + + + + + + + + + + + + + + trace
y-amino butyric acid** 200 50 400 300-500 250 200 200 >
ENZYMES***(79' 88' 96, 130~3) o
Decarboxylase (dopa) 20 30 420 200 130 220 100 70 10 H
HM
Dopamine-/?-oxidase trace 0-8 1-1 trace <
(dopamine)
>
Catecholamine-O-methyl- 80 100 100 90 110 1 9 40
transferase (adrenaline) 5
Monoamineoxidase (serotonin) 800 400 900 1600 900 800 900 1100 900 m
Function of cerebral region Conscious­ Nerve Integra­ Emotions Sensations Motor Sensory Sensory Muscle o
ness, fibres tion of (pain, func­ and and co-ordi­ G
Z
speech be­ motor plea­ tions motor motor nation,
Ö
associa­ tween func­ sure) nerves nerves equili­
tions, the tions brium
motor, cerebral
and hemi­ >
sensory spheres 2!
relays
* Trace = 0-015 //g/g tissue; + = 015-0-30; + + = 0-30-0-60; + + + = 0-60-1-5; + + + + = 1-5-15.
** y-amino butyric acid in /zg/ml.
*** The figures signify the enzyme activity in microgram substrate per gram tissue per hour. The substrates are in brackets.
BIOCHEMISTRY 5
quantities and are quickly reduced by the highly active decarboxylase. So far
dopa has been found in man in normal brain tissue/147' 269) spinal cord,(272)
tissue of phaeochromocytoma(178) and ganglion neuroma,(1415) in urine of
TABLE 2. DECARBOXYLASE ACTIVITY AND PROPORTION OF AMINES IN DIFFERENT
INTESTINAL REGIONS AND IN LIVER, SPLEEN AND SKIN OF HUMANS
Tissue Decarboxylase activity Proportion of serotonin
(5 -hy droxy tr y ptophane) Og/g tissue)
Mucosa of small intestine 3* L(a) 3-7 (duodenum) R
2-9 (ileum) R
Mucosa of colon 1* L(a) 17 R
Appendix 23t G 1 G
Liver 00000010 3 f\ * Lw(ub). up to 10 B
Spleen—healthy subjects ~0·34 U <01 U
Spleen—mastocyte system ~0·2 U 012 U
disease
Decarboxylase activity Proportion of histamine
(histidine) (//g/g tissue)
Spleen—healthy subjects ~70§ U <3·4 U
Spleen—mastocyte system ~500§ U 7-1-180 U
disease
Skin—healthy subjects 70 D
84
Skin—"unaffected" areas of 20Î D 16-2 D
urticaria pigmentosa patients 20-9
Skin—urticaria pigmentosa 160Î D 70-3 D
affected focus 37-9
* Decarboxylase activity in //mol C0 ///mol tissue-N/60 min.
2
t Decarboxylase activity in μ% serotonin produced/g tissue/60 min.
% Decarboxylase activity in μ% histamine produced/g tissue/180 min.
§ Decarboxylase activity in μ% histidine decarboxylated/g tissue/90 min.
L(a) Equivalents according to Langemann and co-workers.(103)
L(b) Equivalents according to Langemann/75)
G Equivalents according to Giarman and co-workers.(112)
R Equivalents according to Resnick and co-workers.(135)
B Equivalents according to Blumberg and co-workers.(136)
D Equivalents according to Demis and co-workers.(677)
U Equivalents according to Ultmann and co-workers.(1832)
neuroblastoma patients/150' 325' 1415"17' 1833> after (oral) tyrosine absorp­
tion tests in cases of tyrosinosis,(156) also, according to own investigations,
in the blood of a young female uraemic and diabetic patient.(725) The hy-
droxylation of tryptophane to 5-hydroxytryptophane was first shown in liver-
homogenates of rats,(157) in bacteria/158, 159) and in glandular extracts of
6 BIOLOGICALLY ACTIVE AMINES FOUND IN MAN
toads previously fed with labelled tryptophane.(77) In man, 5-hydroxytrypto-
phane so far has been found in tumour tissue/116,160, 538) and in the urine
(116, 137, 138, 160-5, 235, 238, 1463, 1887) Qf patients with carcinoids of the
stomach or the intestine/116· 138'161"4·235·238) of the bronchi/160·538, 1463)
and in a neuroblastoma.(1887) It has also been found in the urine of patients
with hypertonia/748) in a carcinoma of the pancreas,*(565) and in skin
extracts and exudates of blisters of patients with diffuse mastocytosis or
urticaria pigmentosa.(166)
The hydroxylation of tyrosine into dopa is catalysed by tyrosinase,f(1,108)
that of tryptophane into 5-hydroxytryptophane is probably catalysed by a
specific tryptophane-5-hydroxylase; but other workers(168) were not able to
isolate the latter from the mucosa of the small intestine in rats and guinea-
pigs/141} But recently it was possible by means of isotope techniques to demon­
strate tryptophanehydroxylase in carcinoid tissue as well as in human platelets.
(1864) 5-Hydroxylation of tryptophane seems to be the rate-limiting step
in the synthesis of serotonin/1864) Tryptophanehydroxylase is strongly
inhibited in vivo by /?-chlorophenylalanine/1865) Initial therapeutic trials
with the called drug in carcinoid patients resulted in a marked improvement
of intestinal symptoms but did not prevent the attacks of flushing/1866)
Dopa- and 5-hydroxytryptophane decarboxylase are probably identical.
Both enzymes are similarly distributed in practically all tissues which have
been examined/85, 87, 96,144) and the ratio of activity using dopa or 5-
hydroxytryptophane as substrates remains unchanged even after purifying
the enzyme preparation to a high degree/145) Both enzymes are inhibited
by the same substances/87, 148' 149) 5-hydroxytryptophane competitively
inhibits the decarboxylation of dopa and vice versa/144,146,148) Extracts of
phaeochromocytoma tissues also decarboxylate 5-hydroxytryptophane and
those of carcinoids decarboxylate dopa/87,103,115)
Numerous investigations under varied experimental conditions make it
almost certain that serotonin is synthesized from tryptophane and 5-hydroxy­
tryptophane in animals and in man/77, 81· 82, 116, 121,137"9, 141, 142, 160,
162, 164, 165, 167, 169-71, 174) υ ^ { the catecholamines are biosynthesized
86
from tyrosine and dopa/60, 63> 83, 118, 179"90> This statement does not
exclude other ways of formation.
Some workers(173, 174) have failed to reproduce the hydroxylation of
tryptamine to serotonin by liver microsomes of rats/172) In addition, in
in vivo experiments with rats and rabbits the intraperitoneal injection of
tryptamine and labelled tryptamine respectively did not cause a rise in the
* With carcinoid syndrome.
f The anomalous pigmentation in albinism is based on a genetic inability of the melano-
cytes to synthesize tyrosinase;(205) the anomalies of phenylketonuria are probably con­
nected, on the one hand, with the inhibition of tyrosinase by phenylalanine, phenylpyruvic
acid, phenylacetic acid, and /7-hydroxyphenyl-acetic acid,(245) and, on the other hand,
with the relative shortage of tyrosine(205, 246) found in this illness.
BIOCHEMISTRY 7
proportion of serotonin in the brain, liver, stomach, intestine, and throm-
bocytes, nor did it promote an increased excretion of 5-hydroxyindole acetic
acid.(174) On the other hand, it seems remarkable that in experiments on
human beings a rise in 5-hydroxyindole acetic acid was observed after the
intramuscular injection of N,N-dimethyltryptamine*(175) as well as after
oral administration of high doses of indole acetic acid.*(176)
Dopamine was produced by incubating liver microsomes of rabbits with
/?- and m-tyramine, noradrenaline, and normetanephrine by incubation with
m-octopamine, and adrenaline by incubation with p- and m-methyloctop-
amine.(4) The injection of labelled tyramine as well as of labelled octopamine
in the intact animal (rat) caused the appearance of labelled noradrenaline
and normetanephrine in the urine.(3) As tyramine is also hydroxylated to
octopamine/191} it is possible that the production of noradrenaline from
tyramine not only takes place via its conversion to dopamine, but also via
its conversion to octopamine. The possibility that octopamine is produced
by the hydroxylation of tyrosine to hydroxyphenylserine with ensuing
decarboxylation is under discussion/189) The production of noradrenaline
from 3,4-dihydroxyphenylserine,(73, 145' 192~201> an amino-acid so far not
discovered in the mammal could be demonstrated both in organ extracts
and in intact animals. Finally, a transamination of 3-hydroxy- or 3,4-
dihydroxyphenylpyruvate to the corresponding amino-acids (m-tyrosin,
dopa), and their decarboxylation to m-tyramine and dopamine was observed
in intact animals (cats)/207, 208) For the time being it is impossible to deter­
mine the importance of the means of formation of catecholamines which
have been referred to here. Of the above-mentioned precursor substances,
p- and m-tyramine/155' 202> 230· 281' 284· 338) octopamine/155·191* 203' 258'
338,1834) and/7-methyloctopamine(155' 203' 258' 338) have been shown to be
constituents of the normal human urine.
Mastocytes of mammals contain a specific l-histidine decarboxylase^12,78'
95, 99) j k j b t j j both in foci and in unaffected parts of the
t as a so een race( n man
skin of patients with urticaria pigmentosa/119' 635, 636, 677) In addition
/-histidine can be decarboxylated by the unspecific "aromatic /-amino-acid
decarboxylase"/95'101) the latter, however, seems to be of minor importance
for the biosynthesis of histamine/95) Besides the specific /-histidine decar­
boxylase, present in the mastocytes, Schayer(102) assumes the existence of
another, biochemically different one, localized in the cells of the micro-
circulatory system, which is activated by non-specific stimuli and produces
histamine as an "intrinsic regulator of microcirculation". The opinion of
Waton(72,151) that insufficient proof for the endogenous production of
* Other authors(177) demonstrated the excretion of 6-hydroxyindole acetic acid after
application of the same substances in human beings. The incubation of tryptamine with
liver microsomes of rabbits led to the production of 6-hydroxytryptamine but not of
5-hydroxytryptamine.(177)