BIOCHEMISTRY

BIOCHEMISTRY

CHAPTER 2 BIOCHEMISTRY I. ORIGIN OF BIOLOGICALLY ACTIVE AMINES 1. General remarks Biologically active amines are produced in man and in animals by b...

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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) a n ( j by tissue(39~103' 1 1 5 ) metabolism. The enzymes which catalyse this process (amino-acid decarboxylases) have pyridoxal-5-phosphate (1 ' 35 ' 37, 38, 68, 69, 74, 87, 91, 93, 94, 105-9, 1835)

as

t h d r

c o m m o n

C OenZyme.

The

questions of stereo- and substrate-specificity of amino-acid decarboxylases are referred to in the appropriate enzymological literature/ 35, 3 8 ' 6 1 ' 1 1 0 ) The animal decarboxylases differ from the bacterial ones in having a lower quotient of activity(1, 61» 1 1 0 ) 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) A m i n o . a c i d 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, aminoacid decarboxylases have been discovered in the kidney/ 53-56 * 61* 7 5 , 1 0 3 , 154* 1455) the liver/ 75 ' 1 5 4 ' 1 4 5 5 ) the spleen/ 1 4 5 5 ' 1 8 3 2 ) the mucosa of the stomach, (80, 1455) t h e i n t e s t i n e (55,103,112) t h e l u n g ) (153, 154, 1455) t h e a d r e n a l m e d u U a j (103) the b r a i n / 9 7 ' 1 1 3 ) the skin/ 1 4 5 5 ) the bone marrow/ 1 4 5 5 ) and the basophil leucocytes/ 1454) Very high decarboxylase activity has been found in carcinoids of the intestine, in their métastases/ 75 ' 76* 87* 1 0 3 ' 1 1 2 ' 114~16> and in phaeochromocytomas/ 8 7 ' 1 0 3 ' 1 1 4 ' 1 1 5 ' 1 1 7 , 1 1 8 ) Histidine decarboxylase occurs in foci and unaffected parts of the skin of urticaria pigmentosa patients/ 119 * 635, 636, 677) a s w e jj a s j n t j s s u e 0 f the cardia and fundus of a patient with a 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/ 6 0 ' 6 3 ' 8 1 ' 1 1 8 · 1 2 0 · 1 2 1 ) 2

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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 tryptophane.(89) Changes which arise in pathological conditions will be considered in the section concerning amine-metabolism and when discussing the amineproducing 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 noradrenaline 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, ( 1 3 4 ) slightly modified)

Cerebrum

Cerebral region: AMINES*< 96 ·

122

'

124

Corpus callosum

Caudate nucleus

Hypo­ thalamus

Thalamus Mid-brain

Pons

Medulla

Cerebellum O

9

>

Dopamine Noradrenaline Serotonin Histamine Acetylcholine y-amino butyric acid** ENZYMES*** ( 7 9 ' 8 8 ' 96, 1 3 0 ~ 3 ) Decarboxylase (dopa) Dopamine-/?-oxidase (dopamine) Catecholamine-O-methyltransferase (adrenaline) Monoamineoxidase (serotonin) Function of cerebral region

trace trace trace trace

++++

trace trace trace

trace

++++

200

50

20 trace

30

80 800 Conscious­ ness, speech associa­ tions, motor, and sensory relays

++++ + ++

++++

++ +++ ++++ ++++ +++

400

+ ++ ++

trace

++++

+ ++ ++ +++

++ +

++

trace trace

++++

250

200

220

100

70

200 1-1

100

100

90

400

900

1600

900

Emotions

Sensations Motor (pain, func­ plea­ tions sure)

Integra­ Nerve tion of fibres be­ motor tween func­ the tions cerebral hemi­ spheres

trace

300-500

420 0-8

130

trace

trace trace trace trace trace 200 10 trace

o O

o > r r > o H

HM

110

1

9

40

< >

800

900

1100

900

m

Sensory and motor nerves

Sensory and motor nerves

Muscle co-ordi­ nation, equili­ brium

* 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.

5 o

G Z Ö

>

2!

5

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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 Mucosa of small intestine Mucosa of colon Appendix Liver Spleen—healthy subjects Spleen—mastocyte system disease

Decarboxylase activity (5 -hy droxy tr y ptophane) 3*

L(a)

1* 23t 00003 \ * 0001 f ~0·34 ~0·2

L(a) G wu. L(b)

U U

Decarboxylase activity (histidine) Spleen—healthy subjects Spleen—mastocyte system disease Skin—healthy subjects Skin—"unaffected" areas of urticaria pigmentosa patients Skin—urticaria pigmentosa affected focus

~70§ ~500§

20Î 160Î

U U

D D

Proportion of serotonin Og/g tissue) 3-7 (duodenum) 2-9 (ileum) 17 1

R R R G

up to 10

B

<01 012

U U

Proportion of histamine (//g/g tissue) <3·4 7-1-180 70 84 16-2 20-9 70-3 37-9

U U D D D

* Decarboxylase activity in //mol C0 2 ///mol tissue-N/60 min. 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 hydroxylation of tryptophane to 5-hydroxytryptophane was first shown in liverhomogenates of rats, (157) in bacteria/ 158, 159) and in glandular extracts of

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BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

toads previously fed with labelled tryptophane. (77) In man, 5-hydroxytryptophane so far has been found in tumour tissue/ 1 1 6 , 1 6 0 , 5 3 8 ) and in the urine (116, 1 3 7 , 1 3 8 , 1 6 0 - 5 , 2 3 5 , 2 3 8 , 1 4 6 3 , 1887) 116

138 161

Q

f

p a t i e n t s

4 235 238)

w i t h

carcinoids of

the

160 538, 1463)

stomach or the intestine/ · ' " · · of the b r o n c h i / · 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 guineapigs/ 1 4 1 } 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, 8 7 , 9 6 , 1 4 4 ) and the ratio of activity using dopa or 5hydroxytryptophane as substrates remains unchanged even after purifying the enzyme preparation to a high degree/ 145) Both enzymes are inhibited by the same substances/ 87, 1 4 8 ' 1 4 9 ) 5-hydroxytryptophane competitively inhibits the decarboxylation of dopa and vice v e r s a / 1 4 4 , 1 4 6 , 1 4 8 ) Extracts of phaeochromocytoma tissues also decarboxylate 5-hydroxytryptophane and those of carcinoids decarboxylate d o p a / 8 7 , 1 0 3 , 1 1 5 ) 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/ 7 7 , 8 1 · 8 2 , 1 1 6 , 1 2 1 , 1 3 7 " 9 , 1 4 1 , 1 4 2 , 1 6 0 , 162, 164, 165, 167, 169-71, 174) υ ^ { 8 6 the catecholamines are biosynthesized from tyrosine and dopa/ 6 0 , 63> 8 3 , 1 1 8 , 179"90> This statement does not exclude other ways of formation. Some workers (173, 1 7 4 ) have failed to reproduce the hydroxylation of tryptamine to serotonin by liver microsomes of rats/ 1 7 2 ) 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 melanocytes 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.

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proportion of serotonin in the brain, liver, stomach, intestine, and thrombocytes, 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-methyloctopamine.(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 3,4dihydroxyphenylpyruvate 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 t k a s a j s o b e e n t r a c e ( j j n m a n both infociand in unaffected parts of the 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 microcirculatory 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)

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BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

histamine exists in cats, dogs, and human beings, and that therefore the histamine in the tissues of the species must originate from the enterai, bacterial decarboxylation of the histidine in food, is opposed by the following findings: after paronteral injection of 14C-/-histidine in cats the production of endo­ genous labelled histamine occurs ; ( 1 5 2 ) histidine is decarboxylated by normal (153,154) a n d b y p a t h o l o g i c a l ( U 9 , 6 3 5 , 6 3 6 , 6 7 7 ) human tissue; finally, the excretion of histamine increases to the same extent in healthy test patients with and without medicamentary inactivation of the intestinal flora after oral administration of histidine. Kakimoto and Armstrong (155) believe that among numerous other amines identified in the human urine (e.g. serotonin, histamine, /?- and m-tyramine), ra-tyramine is the only amine exclusively formed in the intestine. 3. Inhibition of decarboxylation There are compounds, some alien and some indigenous to the body, which inhibit the decarboxylation of amino-acids. The biochemistry and phar­ macology of the numerous inhibitors alien to the bodyi81' 2 0 8 ~ 2 6 ' 273~5» 6 3 4 · 643, 1405-8) w jjj n o t ^ di s c u s s e c i h e r e > Clinical experience of the therapeutic use of such compounds, e.g. for hypertension/ 217, 2 1 9 , 227 " 35 » 276» i*09-i4, 1452,1831) o r c e r t a i n endocrinic active tumours (phaeochromocytoma, neuro­ blastoma, carcinoid)/ 136, 2 3 5 " 4 4 , 2 7 7 , 2 7 8 · 5 2 9 , 8 7 1 , 1282> do not yet permit a conclusive opinion. Among indigenous compounds of the body, for which an inhibitory effect on the decarboxylation of a-amino-acids has been established, phenylpyruvic acid/ 2 1 0 , 2 4 7 ' 2 6 8 ) phenyl acetic acid,(247)/?-hydroxyphenyl pyruvic acid, (210) ra-hydroxyphenyl acetic acid, (210) and /?-hydroxyphenyl lactic acid (210) must be included. These metabolites appear in excessive quantities (39 ' 2 4 8 , 2 5 2 _ 7 ' 270 271) ' in the course of phenylketonuria, an autosomal recessively inherited metabolic disease, which is caused by the inability to hydroxylate phenylalanine to tyrosine. (248_51) It is possible that the reduction of serotonin/ 259, 260) n o r a d r e n a l i n e , and adrenaline/ 216, 2 6 2 ) in the blood, as well as the reduced excretion of 5-hydroxyindole acetic acid/ 2 5 9 , 2 6 0 , 263~7> dopamine, noradrenaline, and adrenaline (262) in the urine found in such patients, could be caused by an inhibition of decarboxylation of the corresponding amino acids by the above-mentioned compounds. So far no results exist which support the inhibition of hydroxylation of tyrosine to dopa or tryptophane to 5-hydroxytryptophane by the compounds which arise in abnormal quantities in the course of phenylketonuria. In addition, 7V-acetyldopamine, which was found in the urine of a phaeo­ chromocytoma patient as well as a neuroblastoma patient/ 1 8 3 7 ) was shown to have an inhibitory effect on dopa-decarboxylase during in vitro experi­ ments/ 7 6 ^

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II. BIOLOGICALLY ACTIVE AMINES FOUND IN MAN Table 3 (pp. 26-56) gives a synopsis of our present knowledge of the occur­ rence of biologically active amines and their metabolites under normal and pathological conditions. In view of the bulk of the results under consideration, a tabular summary seems advisable in order to simplify a survey and comparison. There are, however, some difficulties and doubts in connection with such a tabulation. The data given in technical literature for the normal occurrence differ con­ siderably. One reason for this may lie in the differences in the analytical methods and experimental conditions chosen. Added to this is the difficulty of selective and quantitative determination of amines and metabolites which exist in biological material only in minute concentrations. In the evolution of new methods in research work the possibilities of error, caused by distur­ bing influences and additional effects of related substances, must be taken into more careful consideration. We were convinced of the importance of these factors when working out analytical methods for N,7V-dimethyltryptamine, (488) N5J/V-dimethyl-5-hydroxytryptamine,(638) anc * 5-methoxytryptamine in the blood and urine. (641) In view of the various difficulties inherent in the methods used, some of the normal values given in the table must be regarded as approximations. The abnormal rates in pathological conditions should be regarded as first observations on a limited number of patients—with the exception of the current findings in amine-producing tumors. Frequently it cannot be determined from the results of research as set forth in technical literature, whether they refer to the amine in free form or to its total amount (i.e. free and combined forms); so far a number of compounds only have been demonstrated qualitatively. With regard to the sequence of the specified amine derivatives, Table 3 refers first to the metabolites of oxidation process then to those of other metabolic processes without intending to indicate their magnitude or im­ portance. Common metabolites of different amines are referred to only once. The values given in Table 3 for the normal occurrence of compounds generally indicate a range which would generally agree with the majority of figures quoted in the literature. The findings under pathological conditions are as a rule characterized as "increased" or "decreased" compared with the normal standard; in some instances, e.g. with the amine-producing tumors, the maximum rates so far reported are frequently mentioned. The plus sign used in the table corresponds to the qualitative tracing of a compound. References include all authors who have qualitatively or quantitatively demonstrated the substance concerned. As a supplement to Table 3, a few more findings will be discussed concerning the normal and the abnormal occurrence of the amines or their metabolites. The normal excretion of free phenylethylamine is less than 20 μg per 24 hr,

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BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

but reaches 60 μg per 24 hr during blockade of monoamine-oxidase and simultaneous charge of phenylalanine.(202) In patients with phenylketonuria whose urinary excretion of phenylethylamine did not differ essentially from that of healthy subjects, monoamine oxidase inhibitors increased it to 3000 μg per 24 hr in one experiment(202) and to 190-810 μg per hr in another.(279) The excretion of dopamine significantly increases after the intake of protein.(306) Noradrenahne and adrenaline can be traced in the suprarenal gland of the human foetus from around the third to the fourth month, the former pre­ vailing in quality/ 382 ' 747) in a two-year-old child the concentration of adrenaline is distinctly higher and increases steadily up to old age.(382) The excretion of the two amines increases at first with age,(358, 367) reaching a maximum for noradrenahne between the twentieth and thirtieth year, and for adrenaline between the fortieth and fiftieth year;(358) in infants and small children the excretion of noradrenahne is relatively higher* than in older children.(367) Kärki(358) found no difference between the sexes in the excretion of the two amines, but according to Hochuli(347) the noradrenahne concentration in the plasma is significantly higher in males than in females. The concentration of adrenaline in arterial blood is significantly higher than it is in venous blood, but the situation is reversed for noradrenahne; relative to one another the concentration of adrenaline is significantly higher than that of noradrenahne in arterial blood and lower in venous blood.(348) Fluctuations in the excretion of both amines and 3-methoxy-4-hydroxymandelic acid,(150) their common catabolite, occur every 24 hr being excreted in larger quantities in the day time than during the night/ 357 ' 3 5 8 , 361 ' 372) Apart from that, there is a dependence on the climate, and on the seasons, in the excretion of catecholamines/1427, 1428) When freed from the force of gravity a significant reduction in the excretion of noradrenahne takes place. (1435) Noradrenahne and adrenaline are increased in the blood and urine of healthy subjects after physical* 299 · 343,348, 358, 361, 3 7 3 , 7 3 0 ) and after psychical stress/ 357, 373, 728~30> Under the conditions of acute hypoxaemia Goldring et α/.(1096) and Flohr et α/.(1884) were not able to demonstrate changes of the catecholamine concentration in arterial and mixed venous blood. In the urine of sportsmen after a competition it was found that the excretion of 3-methoxy-4-hydroxymandelic acid had increased considerably. (457, 758) ^ n increase in plasma-concentrations of the two amines was found after hydro- and physiotherapeutic treatments/1808) in patients with angina pectoris after various stresses (physical and psychical/435, 438) also nicotine (731) ) after a shock treatment in psychiatric cases(345) and also after doses of adrenaline given to women in painful and protracted labour.(347) On pas­ sively raising the body into an upright position, there is no increase in the two catecholamines in the blood and urine<344· 348, 359, 361, 364, 732 " 4, 736) * Related to the weight in kilograms.

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(344, 3 4 8 3 6 1 )

' or in some patients with in patients with postural hypotension essential hypertension; (359 ' 3 6 4 , 7 3 3 ' 7 3 4 ) similar observations were made on the excretion of 3-methoxy-4-hydroxymandelic acid in paraplectic patients (455) who had postural hypotension as a result of a high transverse lesion of the spinal cord. Sympathectomized patients (344) or cases treated with gang­ lion-blocking agents (364) showed a normal increase of adrenaline, but an insignificant increase of noradrenaline in the plasma, and in the urine, after having been raised passively into an upright position ; a bilaterally adrenalectomized patient (344) showed a normal increase of noradrenaline but no change in the adrenaline concentration. Independently of alterations of the body's position, decreases in the proportion of adrenaline (258, 7 3 5 , 7 3 6 , 1 4 6 8 ) and increases in that of noradrenaline (735, 7 3 6 ) were found in the plasma and in the urine of bilaterally adrenalectomized patients ; furthermore, an increased excretion of normetanephrine (258) and occasionally of vanillic acid. (258) Alcohol ( 3 6 3 ' 3 6 5 ) as well as nicotine*123, 1 4 2 8 , 1 4 2 9 ' 1 4 6 5 ) cause a large increase in the excretion of adrenaline and a smaller one of noradrenaline. Nearly all the serotonin of the blood is localized in the thrombocytes, the plasma containing only traces under normal conditions/ 4 9 4 ' 4 9 9 ' 5 2 4 ) Newly formed thrombocytes do not contain any serotonin. (1494) It is currently believed that the thrombocytes are not able to produce serotonin. After the recent demonstration of tryptophanehydroxylase in human platelets principally it seems possible that 5-hydroxytryptamine is synthesized in them. (1864) It is probable that serotonin is taken up by the thrombo­ cytes as they pass through the vessels of the gastrointestinal tract, (1494) whose enterochromaffin cells are the main site of production of the extracerebral serotonin. The uptake of serotonin by the thrombocytes is an active process of concentration needing metabolic energy/ 4 9 5 , 7 3 7 ) From findings in carcinoid patients (76 ' 8 1 , 5 4 3 ' 5 5 4 , 7 4 3 ) as well as from saturation experiments in vitro(131~*2) it is clear that human thrombocytes are able to store serotonin far above the normal level.* The excretion of 5-hydroxyindole acetic acid is lower in older people compared with that in people aged 20-40 years. (1426) It is significantly increased by cigarette smoking both in regular smokers (744) and those who do not normally smoke. This is due to the liberation of serotonin by nicotine/ 6 0 5 , 744 ~ 6) In personal investigations (1830) on thirty patients with (decompensated) liver cirrhosis it was shown, using a fluorescent spectrophotometric method, that in about half of the cases the normal concentrations of histamine and serotonin were exceeded in the blood and the 24 hr urine. With decreasing frequency, increases in the * Further details—in particular the question of how energy is provided for the uptake of serotonin by the thrombocytes, which factors increase or inhibit the storage, the liberation of serotonin under physiological, pathological, and pharmacological conditions—are to be found in a recent summary by Erspamer.( 142) Many of these questions still need clarification. Their investigation presents great difficulties, so that definite statements concerning man are not yet possible.

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BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

concentrations of tryptamine, bufotenine, 5-methoxytryptamine, noradrenaline, dopamine, dimethyltryptamine, and adrenaline were seen. Similar changes were seen in seven hepatitis patients examined in the same way.

I I I . METABOLISM AND INACTIVATION OF BIOLOGICALLY ACTIVE AMINES Present knowledge indicates that the metabolism of the biologically active amines is determined mainly by a few elementary types of enzymatically catalysed reactions, i.e. hydroxylation, 0-methylation, N-methylation, Nacetylation, and oxidative deamination. Furthermore, for the inactivation of amines, conjugation and storage are of importance.

1. Metabolism of certain amines The most important metabolic pathways for tyramine, dopamine, noradrenaline, adrenaline, tryptamine, serotonin, and histamine will be discussed to the extent that they appear probable in man. This probability is based on the fact that the metabolites (Table 3) corresponding to the enzymes involved have been demonstrated in man. Tyramine (Fig. 1) /7-Tyramine is oxidized to octopamine (4 ' 1 9 1 , 2 0 3 ' 7 5 9 ) by dopamine-jS hydroxylase* causing hydroxylation of the carbon atom of its side chain. Octopamine is converted to /?-hydroxymandelic acid (298) either directly or after being methylated to 7V-methyloctopamine.(760) The introduction of an OH group in the meta or para position in the nucleus of p- and m-tyramine respectively leads in vitro to the production of dopamine ; (4) it is not known if this reaction also takes place in man. Similarly, the conversion of octopamine to noradrenaline by the addition of an OH group to the nucleus has not been proved yet in man. /7-Tyramine is transformed into jY-methyltyramine(767) by means of an unspecific 7V-methyltransferase, for which S-adenosylmethionine is needed as co-factor and which methylates numerous endogenic and exogenic amines.t p-, m-9 and o-tyramine are oxidatively deaminated to the corresponding hydroxyphenyl acetic acids; the amineoxidases, which * The dopamine-/?-hydroxylase, which utilizes ascorbic and fumarie acid as co-factors/761} is a relatively unspecific enzyme which reacts with many substrates, such as phenylethylamine,<759' 762 · 766 · 1862) p- and m-tyramine,<191· 2 0 3 · 7 5 9 · 766> dopamine/ 761 · 766) 3methoxytyramine,<759' 1862) a-methyl-tyramine,(766) a-methyldopamine,(759·766) Nmethyldopamine,(759· 764~6> mescaline,(766) etc. f For example phenylethylamine, p- and m-tyramine, octopamine, catecholamines, tryptamine, serotonin, N-methylserotonin, mescaline, normorphine, etc.

13

BIOCHEMISTRY CHOHCOOH HO p-Hydroxymandelic acid

CHOHCH,NH 2

Noradrenaline

HO HO Dopamine

a



HO N-Methyloctopamine

Octopamine

CH 2 CH 2 NH 2

CHOHCH 2 NHCH,

CHOHCH 2 NH 2

^^/CH2CH2NH

^ ^

2

H O \ ^ p-Tyramine

^/CH 2 CH 2 NHCH 3

HO N-Methyltyramine

CH2COOH HO^ p-Hydroxyphenylacetic acid

FIG. 1. /?-Tyramine metabolism.

catalyse this process, will be referred to subsequently in more detail in view of their importance for the catabolism of amines indigenous to the body. Dopamine (Fig. 2) Biologically the most important metabolic pathway for dopamine is the hydroxylation of its side chain giving noradrenaline. The reaction is catalysed by dopamine-jS-hydroxylase. N-acetylation of dopamine gives iVacetyldopamine/ 335, 3 3 6 , 1 8 3 6 ) a powerful inhibitor of dopa-decarboxylase. (768) JV-methylation gives epinine(= JV-methyldopamine) which has not so far been shown to occur in man, this may be subsequently hydroxylated in vitro to give adrenaline/ 759, 7 6 4 ' 7 6 5 ) Dopamine is deaminated oxidatively to 3,4-dihydroxyphenylacetic acid ( = homoprotocatechuic acid); (769, 7 7 0 ) from this homovanillic acid is derived, which is the main catabolic product of dopamine metabolism. The latter step is catalysed by the enzyme catechol-0methyltransferase. Catechol-0-methyltransferase was found in normal human liver (771) and in tissue of neuroblastoma. (870) Its occurrence in phaeochromocytomata, as in organic tissues which normally contain nor­ adrenaline (e.g. the heart, brain, and suprarenal glands), is probable in view of their capacity to methylate catechol derivatives (118) after adding Sadenosylmethionine. Experiments using tritium-marked adrenaline and a

16

CH30

CH2CH2NH2

ί

Homovanillic acid

5 P . CH2CH2NH2

HO 3-Methoxytyramme

3,4-Dihydroxyphenylacetic acid

U HO

'2,4,5-Trihydroxyphenylethylamine Η Ο , / ν ^ CHOHCH.NH, HO 3-Methoxy-4- hydroxyphenylethanol

Dopamine

>^

HO S ^ s ^ CH2CH2 NHCOCH3

N-Acetyldopamine

HO,\^J Adrenaline

Noradrenaline

H o ^ ^ /

ÇH2CH2NHCH3

N-Methyldopamine

FIG. 2. Dopamine metabolism.

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

CH 3 0^ 3,4-Dimethoxyphenylethylami ne

cjj o ^ s ^ ^ C ^ C O O H

15

BIOCHEMISTRY

ferment inhibitor suggest an increased activity of catechol-0-methyltransferase in patients with a neuroblastoma.(873) The specific enzyme for catechols needs bivalent cations and S-adenosylmethionine as cofactors. It is inhibited by heavy doses of thyroxine(772) among other things. By (9-methylating dopamine 3-methoxytyramine results/ 769 ' 770) which is deaminated oxidatively to homovanillic acid, or it can be O-methylated to 3,4-dimethoxyphenylethylamine or methylated and oxidized to 3-methoxy-4-hydroxyphenylethanol. Noradrenaline (Fig. 3) 7V-methylation of noradrenaline leads to adrenaline and JV-acetylation to iV-acetylnoradrenaline. By O-methylating noradrenaline normetanephrine is COOH

Yanillic acid

»u

CH>0(r^r/CmmOOÌÌ

CH

Hok^ Protocatechualdehyde

3,4-Dihydroxymandelic acid

^'i

U

HO/^^v/

C H O H C H

U

ahO/^/

CiiOHCH m

>

3 Methoxy-4-hydroxyphenyl ethyl glycol

^

O H

3,4 Dihydroxyphenylethylglycol

u = »u

HO/\/ HO

a , O H C H

Normetanephrine

CHOHCOOH

HO,

^^/

„U

3· Methoxy-4-hydroxymandelic acid

P

C H O H C H

2

N H

2

} 1 0^

^^CHOHCH2NHCH3

HO^ Adrenaline

a

CHOHCH2NIICOCH3

N-Acetylnoradrenaline

FIG. 3. Noradrenaline metabolism.

produced (727,773_9) which is oxidatively deaminated to 3-methoxy-4hydroxymandelic acid (446 ' 727 ' 744~776) and, to a smaller extent, to 3-methoxy4-hydroxyphenylglycol.(727' 775 ' 7 8 0 , 781) The last-named compound, which also originates from noradrenaline by means of O-methylation of 3,4dihydroxyphenylglycol,(778) is possibly converted to vanillic acid.(727) One

16

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

of the main catabolic pathways for noradrenaline gives 3,4-dihydroxymandelic acid by oxidative d e a m i n a t i o n / 7 2 7 ' 7 7 4 , 7 7 6 , 7 7 8 ) By (9-methylating 3,4-dihydroxymandelic acid, 3-methoxy-4-hydroxymandelic acid is pro­ duced/ 7 7 4 - 6 ' 7 7 8 ) The latter is apparently further degraded to vanillic acid (782,783,1433,1850) v i a 3_methoxy-4-hydroxybenzaldehyde (vanillin) (1850) and was proved in the course of incubation tests on animal and human liver. In this case, 3-methoxy-4-hydroxyphenylglyoxylic acid, which is formed by dehydration of the 3-methoxy-4-hydroxymandelic acid, may be assumed as an intermediary stage/ 1 8 5 0 ) The protocatechualdehyde lately found in human urine (335 ' 3 3 6 ) is looked upon as a precursor of the catabolism of 3,4-di­ hydroxymandelic acid to 3,4-dihydroxybenzoic acid. (336)

σ

Adrenaline (Fig. 4) ΓΟΟΗ

Vanillic acid

^ θ /

5

^ /

CHOHCOOH

CHOHCH 2 NHCH 3

U

CH 3D0

3 Methoxy-4 hydroxymandelic acid

^

CHOHCH,OH

CH

^ T

i°,

HO 3-Methoxy 4- hydroxyphenylglycol

Metanephrine

CHOHCH 2 N(CH,) 2

/ C H 3°,

HOv N-Mcthylmetanephrine

^

-.

CHOHCOOH

UO^^/

Hok^

/

3,4-Dihydroxymandelic acid

Η0

Adrenaline

_

-

Hok^ N Dimethylnoradrenaline

CHOHCH 2 NHCH,

Γ^Υ^

CHOHCH 2 N (CH,)->

ΗΟΓ-/^γ/

/

HO^ 3,4-Dihydroxyphcnylglycol

CHOHCH.NHCH (CH,)2

ΗΟ/^γ^ Isopropylnoradrenaline

/CHOHCH.OH

HO^

CHOHCH,NHCH (CH3)2

CH.O^ 3 Methoxyisopropylnoradrenaline

FIG. 4. Adrenaline metabolism.

The catabolism of adrenaline takes place in a way analogous to that of noradrenaline. After O-methylation to metanephrine/ 771 ' 7 7 3 , 7 7 4 ' 7 8 4 ) or by

BIOCHEMISTRY

17

0-methylation after direct oxidative deamination to 3,4-dihydroxymandelic acid/ 774 ' 775 ' 785) it is converted to 3-methoxy-4-hydroxymandelic acid/ 446 ' 774, 784, 785) ^ j ^ j s probably further metabolized to vanillic acid, as has already been mentioned. There are several byways of adrenaline metabolism; one gives rise to 7V-dimethylnoradrenaline,(445) which is transformed by Omethylation to TV-methylmetanephrine (= 7V,iV-dimethylnormetanephrine). (445, 786) another gives 3,4-dihydroxyphenylglycol, which by O-methylation yields 3-methoxy-4-hydroxyphenylglycol.(787' 1816) Finally, it might be converted to isopropylnoradrenaline, which can be methylated to 3-methoxyisopropylnoradrenaline/293'445) iV-methylmetanephrine and 3-methoxy-4hydroxyphenylglycol can also be formed from metanephrine/780' 785, 787) the former by 7V-methylation, the latter by oxidative deamination. It has been mentioned already that 3-methoxy-4-hydroxyphenylglycol is possibly metabolized to vanillic acid.(727) Serotonin (Fig. 5) 5-Hydroxytryptamine is deaminated oxidatively to 5-hydroxyindole acetic acid. In addition, 5-hydroxytryptamine is catabolized in substantially smaller amounts by reduction to the corresponding alcohol, 5-hydroxytryptophol, (1868-70) ^yhjch j s excreted in the free form and combined as the glucuronide or sulphate.* 7V-Methylation of 5-hydroxytryptamine gives 7V-methylserotonin,(767) which can be methylated further to 7V,iV-dimethylserotonin (= bufotenine).(767) The 7V-methylation is catalysed by a relatively unspecific N-methyltransferase.(767) By acetylation of 5-hydroxytryptamine TV-acetylserotonin is produced,(579) which is an intermediary product in the course of the melatonin synthesis (= 5-methoxy-7V-acetylserotonin).(788) The pro­ duction of 5-methoxytryptamine,(489' 641) which we were able to demonstrate in normal human blood and urine, seems to occur fairly easily by deacetylation of melatonin, whereas a direct O-methylation of serotonin to 5-methoxytryptamine, at least in vitro, takes place to a substantially smaller extent.(788) Tryptamine is oxidatively deaminated to indoleacetic acid. 7V,iV-dimethyltryptamine/488' 489) found by us in human blood and urine, is probably produced by methylation of the mono-methyl derivate, which so far has not been traced in man. Histamine (Fig. 6) The oxidative deamination of histamine, in the course of which imidazolacetic acid is formed, is catalysed by diamine-oxidase and also by monoamineoxidase.(790) By means of a specific histamine-N-methyltransferase,(791_3) histamine is transformed into l,4-methylhistamine,(153) which is further * Normally in man about 98% of 5-hydroxytryptamine is catabolized by oxidative deamination and only 2% by reduction to 5-hydroxytryptophol.(1868· 1869) Intake of ethyl alcohol raises the excretion of 5-hydroxytryptophol to about 50%. (1869)

16

CHUCOOH

HO

CH.CH 2 NH,

CH,0

NH

CH.CH HO

NH

5-Methoxytryptamine

NH N-Methyl-5- hydroxytryptamine

5-Hydroxytryptamine

CH 2 CH 2 NHCOCH 3

H 3 CO,

CH,CH,NH 2

HO

NH 5-Methbxy-N- acetyl serotonin

,CH 2 CH 2 NHCOCH 3

HO,

NH N-Acetyl-5- hydroxytryptamine

FIG. 5. Serotonin metabolism.

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

NH 5-Hydroxindoleacetic acid

BIOCHEMISTRY * CH.COOH HN \ ^ N îmidazoleacetic acid

. CH.COOH N H,CN 1,4-Methylimidazole acetic acid

CH.CH.NH,

CH 2 CH 2 NH 2

H N \ ^ N Histamine

H,CN 1,4-Methylhi stamine

CHXH.NHCOCH

N-Acetylhistamine

CH 2 CH 2 NHCH 3

N-Methylhistamine

CH^CH2N(CH3)2

N,N-Dimethylhistamine

FIG. 6. Histamine metabolism.

degraded to 1,4-methylimidazolacetic acid; (153, 6 7 7 ' 6 9 7 ) the latter seems to be quantitatively the most important product of histamine metabolism in (673) in its side chain to m a n (677, 697, 1806) p i n a n y j histamine is methylated N-methyl- and NjN-dimethylhistamine, or acetylated to iV-acetylhistamine. (697,789)

2. Oxidative de-amination For most aromatic and aliphatic amines indigenous to the body, oxidative deamination represents one of several, or the main catabolic pathway. Oxidative deamination is catalysed by monoamine- and diamineoxidases, and is dependent on 0 2 < 794 · 7 9 5 · 798 " 807 > and on pH. ( 2 9 · 3 1 · 7 9 4 " 7 ) The importance of oxygen tension for the inactivation of amines will be discussed in more detail in the chapter on pathophysiology. The monoamineoxidases deaminate alkylamines, (800_2) phenylalkylamines, (soi, 802, 806, 808-10) hydroxyphenylalkylamines, ( 4 7 ' 1 0 7 ' 795> 7 9 6 ' 8 0 1 " 3 · 806* 808 23) " and indolylalkylamines/ 79 ' 7 9 5 ' 8 0 6 · 8 2 3 · 8 2 4 ) This oxidative deamina­ tion takes place with varying rapidity, depending of the length of the alkyl chain (800 ' 8 0 7 ' 8 2 5 ) or on the substrate being a primary, secondary, or tertiary amine. (801) It is possible that various monoamineoxidases exist/ 79, 8 0 7 , 825 7) ~ as differences of activity depending on the origin of the enzyme (species, organ) have been observed in relation to the same amine. Diamineoxidase, on the other hand, which must be clearly distinguished from the monoamine­ oxidases and which was characterized originally as histaminase (799) on

20

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

account of an assumed specificity for histamine, deaminates putrescine, cadaverine, and other polyamines/ 3 1 ' 5 5 ' 8 0 5 ' 8 0 7 ' 8 2 5 ' 827"36> Thus rapidity of deamination and substrate affinity do not run p a r a l l e l / 3 1 ' 8 2 5 ' 8 3 1 ) Some authors ( 8 5 1 - 6 ) assume that diamineoxidase and histaminase are not identical; it is believed that the latter specifically catalyses the break-down of histamine and that of its ring-iV-substituted dérivâtes/ 856) The diamine­ oxidase probably represents a group of closely related homologous enzymes. (825) Lastly, diamines are said to be substrates of monoamineoxidase if one of the two basic groups is substantially weaker than the other/ 8 57) The diamineoxidases/ 847 ' 8 4 8 ) and probably the monoamineoxidases/ 849 ' 8 5 0 ) need pyridoxalphosphate as their co-enzyme. Amineoxidases are widely distributed in the animal world and occur in almost every o r g a n / 4 7 · 5 5 ' 6 7 ' 7 9 ' 1 3 3 ' 7 9 4 " 7 ' 7 "- 8 0 3 > 8 0 5 > s 08 " 11 · 816> 8 1 7 > 8 1 9 · 820,822,826-45,980) Diamineoxidase has been found in numerous nonpathogenic bacteria, but not in pathogenic ones; (29 ' 3 1 ) this observation is of importance in so far as pathogenic bacteria can, for example, produce considerable amounts of histamine, and are not able to detoxicate it/ 2 9 , 8 4 6 ) In man monoamineoxidase has been demonstrated in the kidneys/ 56 ' 7 5 ' 803, 813, 814, 827, 831, 845, 858) | j v e r (75, 803, 814, 827, 872, 976) 814 845 859 860)

( 8 2 7 , 830, 861) j

(153, 827. 830)

uter

827 861

o a n c r e a s

(1499)

intestine/ ' · ' stomach/ brain/ ' > lung/ ' ' 862' 872) 806 815 827 1462) 813) 813) placenta/ ' ' ' thyroid gland/ thymus/ skeletal muscles/ 813) muscles of the heart/ 8 1 3 ) muscles of the bladder/ 8 1 3 ) uterus/ 8 0 6 · 813) and in blood vessels/ 8440 In the serum of patients with cardiac insuf­ ficiency, an increased activity of monoamineoxidase was found, showing parallelism between the degree of insufficiency and the activity of the enzymes. (1859) j n c a r c i n o i d métastases a decreased proportion of monoamineoxidase occurred in comparison with the surrounding (liver- and lung-) parenchyma. (75, 76, 114, 813) similar observations were made in tissue of phaeochromocytoma (114 ' 8 6 4 ) and in a pneumonic lung/ 8 1 3 ) In female patients with toxaemia of pregnancy, the average monoamineoxidase concentration of the placenta was found to be lower than in healthy women/ 1 6 9 5 ' 1 8 7 8 } In patients with thyrotoxicosis, a decreased content of tissue monoamineoxidase was detected in samples of the small intestinal mucosa obtained at biopsy. Simultaneously the excretion of tryptamine and tyramine was increased/ 281) After stopping medication with thyroxine in a case of hypothyroidism, the activity of monamineoxidase in the tissue increased again/ 281} The hyperserotoninaemia and the decreased excretion of 5-hydroxyindole acetic acid, observed in some patients with functional gastrointestinal disturbances, is said to be caused by a decrease in activity of amineoxidase/ 571 ' 8 7 4 ' 8 7 5 ) In the globus pallidus of schizophrenic patients an increased activity of monamineoxidase was detected/ 864) Diamineoxidase in man has been traced in the kidneys/ 72 ' 7 9 4 ' 8 0 3 ' 8 2 7 ' 8 3 0 ' 831> liver/ 803 ' 8 2 7 ' 830> intestine/ 55 ' 72> brain

845)

us/31)

813 827

placenta/31'827'829'830'

21

BIOCHEMISTRY 830

830 840)

31

830

852, 865-7) p ancre as,< > suprarenal glands/ ' blood or serum/ · ' 865, 867, 868) a n d j n t h e m[nQpu 869) Dimrig pregnancy the proportion of histaminase in the serum is increased/ 6 7 1 ' 8 5 2 ' 8 6 8 ' 9 7 8 ' 9 7 9 · 1 4 6 1 ) In recent times the amineoxidases have also aroused interest in their pos­ sible value as therapeutic agents. For instance, histaminase therapy has been used in cases of extensive b u r n s / 8 8 4 " 8 ' 9 4 1 ) There are numerous compounds alien to the body which are able to inhibit the amineoxidasesS816~S3) Such inhibitors are used to clarify questions of amine metabolism, to detect amines which cannot be found under normal conditions—or only as traces, and for therapeutic purposes. Certain psy­ chiatric and internal illnesses, such as depressions/ 889-915 * angina pectoris, (916-28,992) a n c j hypertension/ 235 ' 929 " 32 > were looked on as the main indications for a treatment with monoamineoxidase-blocking agents.

3. Oxidation of ring components Besides the deamination of side chains, catalysed by amineoxidase, an oxidative degradation of the ring component of certain aromatic amines has been shown in vitro, namely for noradrenaline/ 816 ' 9 3 5 ' 9 3 6 ' 9 7 1 ) adrenaline, (8i6,935,936,970,97i) serotonin/ 9 3 3 ' 9 3 7 ' 9 7 1 " 4 ) and bufotenin/ 937 ' 975 > Adrenochrome is produced from adrenaline, noradrenochrome from noradrenaline, and products similar to quinone, which have not yet been clearly defined, derive from serotonin and bufotenin. Cytochromoxidase (816 ' 9 3 7 ) and ceruloplasmine ( 9 3 5 ' 9 3 6 ' 9 7 1 ~ 3 ' 9 9 0 ) are the catalysing enzymes. So far it is not known whether such a catabolism also takes place in vivo, especially in man. Some workers (939) have not been able to confirm the presence of adrenochrome in human serum. (938) Ceruloplasmine is a normal component of the human serum. (940)

4. Further possibilities of inactivating amines indigenous to the body Conjugation with sulphuric, or glycuronic acid/ 6 0 , 1 5 5 ' 3 0 5 ' 5 8 0 , 1 5 7 4 ) represents an important and effective way of inactivating naturally occurring amines and their metabolites. Furthermore the organism can also excrete the amines in an unchanged form.

5. Storage of amines indigenous to the body Naturally occurring amines are stored in the cells of the blood and tissues; they are thus temporarily inactivated and withdrawn from the circulation. It is assumed that each amine can be stored in several types of cells. Those

22

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

cells, in which amines are produced, also seem to have special capacities for storing them ; the chromaffine cells, for example, of the medulla of the suprarenal gland, and the postganglionic sympathetic nerves contain a considerable amount of catecholamines, the mastocytes histamine, and the enterochromaffine cells serotonin. In addition, a considerable number and quantity of amines is found in the blood cells; human thrombocytes, for instance,contain serotonin/ 8 1 ' 4 9 3 " 8 ' 5 0 1 > 5 0 3 · 506,508-i2,515, 517-21,933) n o r _ adrenaline, (340) adrenaline, (340) and histamine; (494, 9 3 4 ) erythrocytes contain serotonin (76) and histamine/ 6 4 7 ' 6 4 8 ' 6 6 0 ) and leucocytes (especially the basophilic ones) contain histamine. (934) The actual storage of amines evidently occurs mainly in the cytoplasmic granules. ( 1 0 7 ) In animal cells it was found that d o p a m i n e / 9 4 3 , 9 4 4 ) noradre­ naline* 9 4 3 , 945-50, 977, 1471-3) adrenaline ( 9 4 3 , 9 4 5 ' 9 4 6 ' 9 4 8 _ 5 0 ' 9 7 7 ' 1*70-3)

serotonin, (951 - 5) and histamine*684* 9 4 6 ' 954* 9 5 6 ' 9 5 7 ) are stored in granules. Examinations of the normal medulla of the human suprarenal gland and of tissue from a phaeochromocytoma showed that two-thirds of the noradrenaline and adrenaline are stored in granular elements, one third in the cytoplasm. (385) j n c a r c i n o i d c e ii s serotonin was found in the specific granules (586) and in granules and ground substance. (942) According to electron-microscopic examinations of normal human platelets, serotonin is contained almost exclusively in the hyalomere. (933) According to Tranzer (1875) serotonin of human platelets is probably stored in the a-granules. Adenosine triphosphate* 737 ' 9 5 5 ) seems to be of importance for the binding of serotonin, for that of noradrenaline and adrenaline adenosine triphosphate (385, 948, 949, 960, 961, 1471) a n d r i b o n u c i e i c a cid, (950) and for the binding of histamine heparin,* 962-6, 9 9 1 ) adenosine triphosphate, (966) and perhaps also phospholipids/ 684 ' 9 6 7 " 9 ) The molar proportion of catecholamines to adenosine triphosphate in the medulla of the normal human suprarenal gland is about 1: 4-5, ( 3 8 5 ) whereas in tissue from a phaeochromocytoma a proportion of 1:10-35 was found. (385) This observation, coupled with that of decreased granular storage of cate­ cholamines in the cells of a phaeochromocytoma/ 117 ' 1 4 6 9 ) point to a dis­ turbance in the storage mechanisms of cells from chromaffine tissue tumours. (989, 1469) rpj^ j n c r e a s e ( j secretion from such tumours is probably connected with this disturbance. IV.

INCORPORATION OF BIOLOGICALLY AMINES INTO BODY PROTEINS

ACTIVE

Recent in vitro experiments have demonstrated the possibility that biolo­ gically active amines may be incorporated into the body protein. Using iso­ topes, it was shown that phenylethylamine, (982_5) putrescine, histamine, cadaverine, colamine, methylamine, noradrenaline, and 5-hydroxytryptamine

BIOCHEMISTRY

23

(985) w e r e j n c o r p 0 r a t e d into human fibrinogen, serum albumin, animal a-globulin, ceruloplasmine, pepsin, (985) and liver protein. (982-5) The incorporation proved to be governed by an enzymic process dependent on pH, temperature, and concentration of amine. (985) The incorporation of phenylethylamine was greatly increased by tyramine. (982) In vivo an incorporation of this kind was proved for mescaline, but the latter compound has not so far been found in animal. (986) Obviously such incorporation processes may be interpreted as inactivations. On the other hand, they may result in the production of compounds with effects of their own. For instance, after giving mescaline, a neurovegetative, then a hal­ lucinatory phase is observed both in man and in animals. The temporal correspondence between these phases and the respective maxima of free, and protein-bound mescaline has been measured in animal experiments and it was found that the first phase is consistent with a direct effect of mescaline, and the second with that of the mescaline protein. (986) V. AMINE TURNOVER So far little is known about the rate of amine turnover. Taking a concentration of 5-hydroxytryptamine of 0-05 ^g/ml in the blood and an excretion of 3-6 mg per day of 5-hydroxyindole acetic acid as a basis, Erspamer (987) estimated that the amount of 5-hydroxytryptamine contained in the total blood volume is metabolized every 2-3 hr. Heissel (1493) found that 14 C-marked serotonin in the thrombocytes of eleven healthy subjects had a half-life of 5-6 days. Sjoerdsma et alS81) found a pool of 2800 mg 5-hydroxytryptamine with a half-life of 5^ days in a patient with a metastasized carcinoid of the small intestine after intravenous injections of 1 4 Cmarked hydroxytryptophane. Zucker et alS1A92) found a half-life of 1-7-2-8 days for labelled serotonin in the thrombocytes of a patient with multiple sclerosis; in a patient with an inactive endocrine rectal carcinoid one of 4-5 days; in five patients with active endocrine carcinoids of the stomach, or the small intestine, half-life rates of 0-12-1-5 days. The serotonin half-life of the thrombocytes, and the excretion of 5-hydroxyindole acetic acid in the patients with the active endocrine tumours were reciprocally proportional. In order to explain the reduced half-life found in carcinoid patients, the authors assumed an exchange of thrombocyte and tissue-serotonin. Adam et alS610) stated that after an intravenous infusion of histamine, approximately 1% of the injected amine is excreted in the urine independently of the rate of the infusion. On the assumption that the free histamine found in the urine under physiological conditions originates from the plasma, the authors presume that approximately 1% of endogenously produced histamine also appears in the urine. Taking an average urinary excretion of 20/ig free histamine per 24 hr as a basis, about 2000 μg histamine per day in free form

24

BIOLOGICALLY ACTIVE AMINES FOUND IN MAN

would therefore enter the circulation in adults. Demis and co-workers(677' 697) injected 14C-histamine intracutaneously and compared the normal 24 hr excretion of free histamine with the percentage of the labelled base which was excreted in the free form. They arrived at a similar conclusion estimating the turnover of histamine globe to 2 mg/day. On the basis of this turnover, the total proportion of histamine in the skin was estimated without taking the extracutaneous histamine into consideration, and the time for total histamine turnover was calculated to 20-30 days. In two patients with urticaria pigmentosa a histamine turnover of about 7 mg/day was noted, and the time for total turnover was 10 days. Pearce and Valentine(700) calculated a turnover of 43-5 mg/day histamine in the blood of seven patients with chronic myeloid leukemia from their mean concentration of 8-7 μg/ml histamine in the blood, and assuming a blood volume of 5 1. and a 24-hr life span for the circulating granulocytes. The analogous rate for healthy subjects would be about a hundred times lower.(700) With regard to /-noradrenaline, von Euler and Luft(350) conclude from the increase in its excretion when continuous intravenous infusions of the drug are given, that about 0-6 μg/min enter the circulation under physiological conditions. The estimate, however, was related only to the excretion of lnoradrenaline, its possible catabolic products not being taken into account. According to Cohen et
BIOCHEMISTRY

25

metabolites to the proportion of the amines and their metabolites in the turnover when they were removed at operation. The results suggested that a high percentage of small phaeochromocytomata generally secreted the amines unchanged into the plasma and replaced their stock of amines relatively quickly. The large tumours metabolized their supply of noradrenaline and adrenaline more slowly, and the greater part of the amines were locally inactivated. In patients with normal or only slightly increased excretion of catecholamines, but with a significantly increased excretion of metabolites, the existence of a phaeochromacytoma with an extensive catabolism of amines inside the tumour could therefore be assumed. In one case the daily production of catecholamines amounted to 725 mg, the total amount of amine in the tumour to 10-6 g, and the necessary amount of amino-acids for the synthesis of these amines was estimated at 20% of the daily intake of tyrosine and 9% of tyrosine plus phenylalanine intake/ 989} In a patient with a metastasized carcinoid, up to 60% of the daily intake of tryptophan in food was used for the production of serotonin/139)

B

TABLE 3. OCCURRENCE OF BIOLOGICALLY ACTIVE AMINES AND THEIR METABOLITES IN M A N UNDER NORMAL AND PATHOLOGICAL CONDITIONS

^

(The plus sign ( + ) corresponds to the qualitative in tracing of a compound)

Occurrence Amine or metabolite

Normal/Pathological

Blood plasma serum (//g/ml)

Phenyl acetic acid

+

j>-Tyramine

normal

+

increased2 increased

»>

> J

liver diseases phenylketonuria

spinal cord

+

O

o > f r

Quantity (Mëlë) 202 202, 279 256 256 1 282, 283 155,202,230,281 284, 338, 1417 285,1 286 206 293 1417

> o H

<

>

2 M

00

►n

O C Ό

+

99

carcinoid hyperthyroidism renal insufficiency

Type

100-600 bile+

phaeochromocytoma tumours of the sympathetic nervous system3

normal

of the body (^g/ml)

References

Tissue

+

»?

/7-Hydroxyphenyl acetic acid

Liquor or

othpi* Al.fluids UXVIO V/lllvl

20 increased

normal phenylketonuria phenylketonuria

Phenylethylamine

Urine 0"g/24 hr)

o r o

+

+

1840 337 281 2871-2911 2921 294,1834

++ ++

295, 1498 255

decreased increased decreased

> z

/7-Octopamine ( = norsynephrine) /7-Hydroxy mandelic acid

N-methyl-/?-octopamine (synephrine, "sympatol")

N-methyl-/?-tyramine w-tyramine

m-Hydroxyphenyl acetic acid ö-Tyramine

normal

up to 330

normal

0-6-2-5 per mg creatinine | 3100

surmise of phaeochromocytoma crises of hypertension in the course of an unknown basal disease normal phaeochromocytoma surmise of phaeochromocytoma tumours of the sympathetic nervous system >> crises of hypertension in the course of an unknown basal disease normal normal

normal liver diseases normal

3700

155,191,203, 258, 338, 1834 296, 297, 1834 298 298

up to 3000

155,203,258, 338

increased 3800

293 298

increased4

293

+

1840 298

+5

155 155

up to 19,400

free: 2-5 per 50 mg creatinine | bound: 2-4 per 50 mg creatinine |

+ +

decreased up to 50

O

o

X m

g C/3

H

155 202, 338 294,296,1834 295, 1498 202

to

TABLE 3—continued

oo

Occurrence Amine or metabolite

o-Hydroxyphenyl acetic acid

Normal/Pathological

Blood plasma serum (//g/ml)

normal

Urine (^g/24hr)

References

Tissue Type

Quantity Oig/g)

257 1498 748 60,262,281,299310, 1415-17 307 307

++ +6

tf-Hydroxymandelic acid Dopamine normal ( = 3-hydroxytyramine)

50-350 free: 66-157 bound: 12-142

» >» phaeochromocytoma

up to 3420

paraganglioma

up to 450

tumours of the sympathetic nervous system

up to 102000

+7

decreased

O

257, 296

30O-1000 per g creatinine increased

phenylketonuria liver diseases

renal insufficiency Parkinsonism

Liquor or other fluids of the body 0*g/ml)

brain

see Table 4 (P. 57)

spinal cord

see Table 5 (P. 61)

tumour

up to 37-2

tumour

up to 1970

tumour

209

124, 144, 147, 269, 275, 311-15,1839 272 178, 302, 307, 316,317 178, 320-2 317 317 150, 309, 318, 751, 1415-17 318, 1023, 1415 644 308, 310, 319

r o o o > r > o H

< >

2

m c/a *n

O C

Ö

> z

Parkinsonism

3,4-Dihydroxyphenyl acetic acid

3-Methoxytyramine

3-Methoxy-4-hydroxyphenylethanol 3-Methoxy-4-hydroxyphenyl acetic acid ( = homovanillic acid)

brain

striate syndrome phenylketonuria maniac phase/ cyclothymia thyrotoxicosis normal

increased decreased increased

phaeochromocytoma tumours of the sympathetic nervous system postural hypotension normal

890 increased

phaeochromocytoma tumours of the sympathetic nervous system >» normal tumours of the sympathetic nervous system normal normal

(increased) 211-378

brain

increased8 free: 0-1 per 50 mg creatinine bound: 0-2 per 50 mg creatinine + increased8 up to about 11400

see Table 4 (P. 60)

311,313-15 308 262 324 281 307, 1416 269, 312 307 150,1416 307 155 155 338, 1415 293, 750 150, 293, 326, 328, 750, 751, 1415 1840 752 328,9 750

+ + increased

'300O-8000

see Table 6 (p. 62)

liquor: -0075

O

o M m

g

c/a H

753 150,277,294, 296, 329, 330, 750, 1415, 1417,1419

to

TABLE 3—continued

o Occurrence

Àmitii* o r TYiPtiìholitp

xVllXlllw yJX. li.Awldl/V/IllV'

Normal/Pathological

Blood plasma serum (^g/ml)

normal

up to 17100

»5

3,4-Dimethoxy phenylethylamine JV-Acetyldopamine

Noradrenaline ( = aterenol, norepinephrine)

Urine « 2 4 hr)

phaeochromocytoma

increased

tumours of the sympathetic nervous system

up to 265000

carcinoid melanoma Parkinsonism normal schizophrenia phaeochromocytoma tumours of the sympathetic nervous system normal normal

increased increased

+

-20-50

+ +

Liquor or other fluids of the body Og/ml)

Tissue Type

brain

brain

Quantity 0*g/g) 2-25-4-47

decreased

R pfprpncp^ XX-wl W l V l l W v o

331 1844, 1845 293, 294, 750, 1419 150, 277, 293 318, 327, 328, 750, 751, 763, 1415, 1417, 1419 751 332 1845 981 333, 334, 1838 335, 336 1837

o r o o o > r r > o H

< >

5 m

•Tri

O

a Ö

0000100045

117,339-49,1883 -15-60

299-302, 304-6, 308-10, 350-79, 1089, 1241, 1245, 1351, 1360, 1415, 1417, 1435

> as

phaeochromocytoma

1843

liquor: 00036

normal

up to 0-144

360 360 -50-250 medulla of suprarenal gland see Table 4 brain (p. 57) spinal cord see Table 5 (p. 61) nerves +

tumour

paraganglioma ?»

tumours of the sympathetic nervous system carcinoid bronchial carcinoid postural hypotension

tumour

tumour tumour

104,117,380-5 144, 147, 269, 275,311-15 272

386 117, 118,348, 379, 387, 388 117,118, 150, 178, 232, 294, 302, 307, 316, 336, 348, 356, 379, 388, 393407, 434, 1425 up to 12000 104,117,118, 150, 178, 294, 316, 348, 385, 387, 393, 397, 403, 405, 431, 1421 317 317 150 309, 318, 377, 408-11, 1415, 1417 318,408,432 up to 70 240 433 0-25 352

o o

S3 w l-H

H

TABLE 3—continued

Occurrence Amine or metabolite

Normal /Pathological

Urine C"g/24hr)

increased10

hypertension hypertension

renal hypertension unilateral stenosis of renal artery hypertension during gestational toxicosis severe eclampsia renal insufficiency »>

Blood plasma serum Og/ml)

increased12 increased increased increased increased13



burns accidents or post­ operative complications Raynaud's disease physical or psychical stress of patients with angina pectoris myocardial infarction

increased

heart insufficiency

increased

»>

>>

increased

11

13

13

increased up to 570 up to 442

Liquor or other fluids of the body G"g/ml)

Tissue Type

Quantity 0*g/g)

References

389, 390 284, 299, 364, 374-6, 378, 390, 394, 412-20 419, 420 294 419 346 644 644 362, 421 354

u

3

r o

2 >

r

> o H

<

ra

>

2 w

on

►fl

O C Ö HM

increased increased

391 435, 438 14

increased increased

435 351,375,437 349 375, 1679

z s

>

emphysema of the lung 1 moderately and chronic asthmoid increased bronchitis bronchial asthma increased liver diseases increased portal hypertension increase in portal vein blood15 hyperthyroidism ulcer infections infectious diseases of the central nervous system schizophrenia

phenylketonuria progressive muscular dystrophy

425 369 427

hyperthyroid struma

decreased increased increased 0006

17

psychoses maniac phase/ cyclothymia state of depression, dysphoria senile dementia alcohol hallucinosis,18 delirium tremens surmise of an organic illness of the brain

425

increased increased

liquor : -00031

1684 428 369 426 392 392 369 324

increased

368

increased increased

368 370, 429 392

0007

decreased

increased16

liquor : 00025 decreased decreased

392 216,261,262 261,262 430

w

o o a m

H

TABLE 3—continued

4^

Occurrence Amine or metabolite

3,4-Dihydroxymandelic acid Protocatechualdehyde Normetanephrine ( = 3-0-methylnoradrenaline)

Normal/Pathological



Urine
Liquor or other fluids of the body (//g/ml)

Tissue Type

Quantity C"g/g)

40-80 up to 3050 7000 <300

normal phaeochromocytoma phaeochromocytoma normal

phaeochromocytoma

3,4-Dihydroxyphenylglycol 3-Methoxy-4-hydroxyphenylglycol

Blood plasma serum (//g/ml)

0027-0045

up to 3000019 tumour

up to 25

References

307,1841 1841 336 150,19 19 155, 202, 203, , 204,19 337, 338, 43919, 440-3, 452, 1415, 1417 387 204, 293, 379, 387, 444, 445 750,1019,1431 321,387,444 293, 410, 750, 1415, 1417

tumours of the sympathetic nervous system in psychotic children normal

increased (increased)

443 727

phaeochromocytoma

16-5 per mg creatinine

750

tumours of the sympathetic nervous system

up to 750 per mg creatinine

+ 20

tumour

5-10

1418 750

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TABLE 3—continued

Occurrence Amine or metabolite

3-Methoxy-4-hydroxybenzoic acid ( = vanii lie acid)

N-Acetylnoradrenaline

Lactylnoradrenaline Adrenaline ( = epinephrine)

Normal/Pathological

Blood plasma serum fag/ml)

>>

Liquor or other fluids of the body (//g/ml)

Tissue Type

Quantity (^g/g)

-1000

normal severe stress phaeochromocytoma tumours of the sympathetic nervous system liver disease phaeochromocytoma tumours of the sympathetic nervous system phaeochromocytoma normal

Urine Oig/24 hr)

References

258, 294, 464-6, 727,22 1432 258, 464, 467 294, 459, 750 750

+

increased increased

o r o o o > r r H-

> o H

increased

295 335, 336 1836

+ 23 +

< >

S

m

tumour

-0000030001 -3-15

liquor : -00012

+

468 262, 340-9, 1883 1843 262, 300, 302, 308, 310, 3502,354,357-65, 367, 368, 3709, 426, 1032, 1089, 1241, 1245, 1351, 1360, 1435

tya

rti

O C3 Z Ö

>

suprarenal gland

normal

brain 24

phaeochromocytoma

increased

coronary nerves coronary arteries muscles of the heart ventricle

carcinoid bronchial carcinoid physical of psychical stress or patients with angina pectoris

increased increased increased increased25

see Table 4 (p. 59) -4-5

104,117,381, 382, 384, 385, 470 269 469

0-0-35

469

0-3

469

up to 5310

tumour

paraganglioma tumours of the sympathetic nervous system

220-950

up to 8170

tumour

1892

tumour

up to 0074

tumour

up to 2

117,348 150, 178, 294, 302, 316, 336, 348, 387, 393, 394, 396-401, 404, 406, 407, 445, 1425 104,117,118, 150,294,316, 348, 385, 393, 397, 403, 405, 431, 1421 385 409 318 318,432 240 433, 560 435, 438

w

3 o

ra

g C/5

* ►<

TABLE 3—continued

oo

Occurrence Amine or metabolite

Normal/Pathological

myocardial infarction »> »> cardiovascular decompensation postural hypotension unilateral stenosis of renal artery renal insufficiency burns accidents, or postoperative complications Raynaud's disease emphysema of the lung, asthmatic bronchitis, bronchial asthma portal hypertension

hyperthyroidism infectious diseases of the central nervous system

Blood plasma serum Og/ml) increased

increased

Urine Og/24 hr)

Liquor or other fluids of the body (//g/ml)

Tissue Type

Quantity Og/g)

R pfîprpnrpç A W l VA v l l t t ü

w O

increased25

435 351,375,436, 437 375

r o o o > r r

decreased increased

352 294

> o

increased26 increased increased

644 362,421,691, 354

increased

391 425

increased25

increase in portal vein blood27

H

< >

TI

O G Z Ö

427

> thyroid gland increased

increased28

1684 426

surmise of an organic illness of the brain

-00023

schizophrenia

-00016

endogenous depressions manic phase/ cyclothymia senile dementia alcohol hallucinosis,30 delirium tremens striate syndrome phenylketonuria Metanephrine ( = 3-0methyladrenaline)

normal

iV-Methylmetanephrine ( = 3-0-methyl-N-dimethylnoradrenaline)

tumours of the sympathetic nervous system normal phaeochromocytoma

liquor: ~ 00009

increased decreased29

decreased

j>

phaeochromocytoma

392

0021

392 392 392

liquor: -000093

471,472

368

increased

324, 368

decreased increased

370, 429

368

increased

308

216, 261, 262

decreased -50-300

OAO

X

g

C/5 zbz H 150, 155, 202, 204, 338, 439-

up to 3140031

increased

u o o

tumour

up to 40 up to 3900 tumour

up to 4-6

42 387 118,204,293, 387, 441, 445, 473, 750, 1019, 1431 321, 387, 1418 410, 750 445 293, 445, 750 445

TABLE 3—continued

Occurrence Amine or metabolite

N-Isopropylnoradrenaline ( = isoprenaline, isoproterenol, "aludrin") 3-Methoxy-JV-isopropylnoradrenaline Lactyladrenaline Tryptamine

Normal/Pathological

Blood plasma serum 0/g/ml)

Urine « 2 4 hr) 1

Liquor or other fluids of the body 0*g/ml)

phaeochromocytoma normal carcinoid >» hepatolenticular degeneration burns »» insufficiency of the kidney uraemia thyrotoxicosis infantile toxicosis pellagra erythrodermia lung abscess depressions

+

increased

30-120 33

84000 decreased34 increased increased35

increased + + + + + + + 1 decreased

References

suprarenal gland

0-6

tumour

+

475 293, 473 468 489 89, 281, 338, 443, 476 477 477 337 1886 691 691 644

33

increased35

Quantity C"g/g)

474

+ 0005-002

Type

5-1032

normal phaeochromocytoma

Tissue

liquor : + 35

490 281 478, 479, 492 491 492 492 1881

o r o

O

o > r r < > o H

l-H

<

M

>

S

W m *ti

O

c

>

3-Indole acetic acid

JV,iV-Dimethyltryptamine Serotonin ( = 5hydroxytryptamine, enteramine)

normal carcinoid hepatolenticular degeneration pellagra phenylketonuria idiopathic sprue infantile toxicosis neuromuscular diseases Hartnup's disease maple syrup disease normal »» normal

(children) (adults)

5200-13800 increased increased

39, 225, 478, 480 244, 477 1886

decreased increased increased

754 255, 263 39,481,482 478, 479, 492 39

++

increased

0039 blood: -01-0-3 serum: -002015 thrombocytes: 0-2-1-3 per 109 thrombocytes erythrocytes: 001-002

increased increased

485, 486 487 488, 489 488, 489 137-139, 244 493-516, 1436

-42-98

O

o X

w 81,493-8,501, 503, 506, 50812, 515, 51721, 933 76

liquor: 003-01 <002

522

40-160 brain foetal brain

see Table 4 (P. 57) 005

498, 523, 1875 139, 155, 165, 338, 443, 476, 524-9 124, 312, 313, 315, 530, 531 532

g e« H ni

TABLE 3—continued

è Occurrence

Amine or metabolite

Normal/Pathological

Blood plasma serum G"g/ml)

Liquor or other fluids of the body feg/ml)

Tissue Type stomach: corpus36 antrum 36 pylorus36 intestine : duo­ denum36 jejunum36 ileum36 caecum36 colon36 appen­ dix36 liver pancreas spleen aorta bronchial mucous mem­ brane skin pineal gland

normal

40

41

carcinoid

Urine 0"g/24 hr)

up to 15

Quantity Gwg/g)

References

37

0-3-1-1 0-5-1-337 0-2-10

135 135 135

2-9^-5 37

135

938

o r o

O o > r r >< > o H

533 135 533 135 112,135

< a >

136, 534 up to l 1463 0-1739 up to 3-0539 535,536 136 + 0-03-0-4539 537, 538

C/3

1-2-4-637 8-1l 38 1-0-2-437 0-4-1-437 39

up to 001 3 9 539, 540 3-2839 541 76,81, 112, 1379,167, 240,

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TABLE 3—continued

Occurrence Amine or metabolite

Normal/Pathological

Blood plasma serum 0/g/ml)

Urine fog/24 hr)

Liquor or other fluids of the body fog/ml)

Tissue Type

carcinoid bronchial

tumour or méta­ stases

tumours of the sympathetic nervous system urticaria pigmentosa bullous urticaria pigmentosa

tumour

carcinoma of the pancreas46 »>

o r o

Quantity fog/g) up to 250

+ 46

O

433, 533, 534, 537, 538, 544, 550, 559, 560, 563, 582, 590-3 432

o > r r > o H

< exudate of blisters : 01-0-5

' *hy per serotoninaemia" increased bronchial carcinoma carcinoma of the gall bladder neoplasm of the pancreatic duct46

References

skin/foci

tumour

1-3

up to 23

20

increased

588,597 576 570, 571, 874, 875 595 564

ffl

>

5m c/a

O C

u

565 increased

métastases tumour or méta­ stases

up to 32 up to ~ 4

565 583 583

> 2

carcinomata of the gastrointestinal tract colon carcinoma idiopathic sprue infantile toxicosis ulcerative colitis extensive intestinal resection resection of stomach liver diseases

decreased

509 tumour

increased decreased48

++ colon

decreased decreased decreased liquor: up to 0025

hepatic coma uraemia >> burns

decreased increased49 increased49

leukaemia

decreased

polycythaemia vera pernicious anaemia aplastic anaemia lymphogranulomatosis primary haemorrhagic diatheses allergies primary chronic polyarthritis Hartnup's disease phenylketonuria mental defects

decreased decreased decreased decreased decreased

increased49

increased decreased decreased increased

604

decreased

exudate of blisters: -01

decreased

585 515, 1436 478, 479 481 596 481, 572 507, 509 507,509,511, 512 523 511,574 644 691 691 577 512, 566, 567, 742 512, 567, 742 512, 567, 742 512, 567 512, 567, 742 483, 501, 504, 511,567-69 514 506,510,511, 573 51 486 259, 260 259, 260, 513

O

o X

m S

C/5

4^

TABLE 3—continued

Occurrence Amine or metabolite

Normal/Pathological

schizophrenia epilepsy epileptic fits

Blood plasma serum (^g/ml)

Urine Gig/24 hr)

decreased decreased

liquor: up to 0035

Parkinsonism normal

normal carcinoid

~200O10000

traces

Tissue Type

Quantity (Mëlë)

liquor: up to 004 increased increased 0-2-30 up to 0-2 up to 003

acute poliomyelitis meningitis tuberculous meningitis brain tumours fresh brain haemorrhages acute brain traumata

5-Hydroxyindole acetic acid

Liquor or other fluids of the body teg/ml)

+ up to 944000

R efprpn ΓΡ^ IvVlvl vll^vO

O

513 513 523

o > r r

1876 1876 522 523, 575 523

> o

523, 575 brain

see Table 6 (P. 62)

o r o

H

< m

>

m

313,531 76, 139, 165, 171, 480, 484, 498, 500, 502, 513, 515, 527, 550, 558, 577, 598-610,1439, 1442^, 1453, 1574 1877 76 76,77,81, 136-9, 163, 165, 167,

O C Ö

2 2

>

carcinoid bronchial carcinoid

carcinoid of the ovary52 urticaria pigmentosa bronchial carcinoma pancreas carcinoma52 pancreas carcinoma52 pancreas carcinoma52 neoplasm of the pancreatic duct52 ' 'hy perserotoninaemia' ' pellagra idiopathic sprue ulcerative colitis

métastases

up to 263000

up to ~182

métastases

up to 99000 |

235, 238, 240, 242-4, 337, 484, 498, 500, 502, 505, 528, 545, 549, 550, 552, 554, 556, 557, 579-81, 594, 601, OH­ IO, 751, 1437, 1439, 1445-9, 1464, 1574 138, 505 160, 533, 534, 537, 544, 553, 559-63, 581, 582,590,591, 593, 595, 61728, 1450, 1451, 1463 538 1847

O

o

m

gc/a Η4

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►<

increased increased increased

increased subnormal decreased increased decreased

576, 597, 631 595, 629 583 583

ascitic fluid : 0-35 métastases

3-6

583 565 570, 571 754 482,484,515 630 481

TABLE 3—continued

Occurrence Amint» c\r mptaholitp

/ ^ . l l l l l l V SJl IIIVICH/VSJIIV

5-Hydroxyindole acetic acid-O-sulphate 5-Hydroxytryptophol

Normal/Pathological

extensive intestinal resection liver insufficiency superficial gastritis infantile toxicosis burns myocardial infarction bronchial asthma lung abscess erythrodermia phenylketonuria Hartnup's disease mental defects with different causes depressions >> mania epilepsy Parkinsonism hydrocephalus carcinoid bronchial carcinoid (oat-cell carcinoma) infantile toxicosis normal

Blood plasma serum 0*g/ml)

Urine (^g/24 hr)

Liquor or

other fluids

of the body 0*g/ml)

Tissue Type

Quantity (Mëlë)

R eferpnrp^

l W l v l VH^VO

decreased

481, 572

decreased decreased

632 604 478, 479 577 633 1442 492 492 259, 260, 263-7 486 486 513 610 1880 324, 610 513 608 1877 498, 580, 637 1463

++

up to 35200 increased increased

++ ++

decreased decreased increased increased increased decreased decreased

+ + + +

decreased

increased

478 1868, 1869

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TABLE 3—continued

o Occurrence

Amitif» fvr mptiihnlitf*

^ V l l l l l l V \JL 111 V ICI l/V-ΊΙ IV

Normal/Pathological

normal

Blood plasma serum (//g/ml)

Urine Gig/24 hr)

neutrophil leuc: 39 per 10 neutr. leuc. thrombocy tes : 001-012 per 109 thromb. erythrocytes : 0004-0-2

Liquor or other fluids of the body 0/g/ml)

Tissue Ti. f»ff*rf»n e pç

Type

Quantity (^g/g)

AVVIVI V i l W O

934

494

o r o

O

o > r r > o H

I—*

647, 648, 660

free: - 5 - 4 0 (2-90) bound: -3-55

679

liquor : -001

saliva: 007

submaxillar gland skin synovial membrane

4-1 4-10

56

3-8

155, 165, 281, 338, 421, 580, 663-78, 696, 757, 1460 1835 1835 539, 540, 636, 657, 677, 6804, 704, 755 1848

< M >

g

5 m c/a •A

O

a >

normal 57

lung: children adults j>

stomach intestines liver spleen brain

57 57

normal58

nerves, ganglia mamma mastocytosis

-6 -25 ~74 10-48 16-65 0-8-3 1-5-3-3 see Table 4 (p. 60) -2-10 0-8-2-2

up to 555 exudate of blisters :

+++

carcinoid

bronchial carcinoid (oat-cell carcinoma)

686 687 1832 549, 635, 674, 675, 692-7 724

O O X m C/3

skin/foci/ tumour

up to 950

spleen liver

up to 1333 up to 1896

tumour or méta­ stases

up to 105

up to 6800

up to 1260

684 684 1457 72 72 72, 685 535 318

588, 597, 636, H 674,684,701, 704 535, 685 685, 702, 720 542, 549 116,138,163, 165, 528, 542, 549, 580, 696, 1463, 1885 116,549,588 1463

TABLE 3—continued

Occurrence Amini* or mf»tflhnlitp

r V l l l l l l W \JL lilt/ICI CVsll IV

Normal/Pathological

tumours of the sympathetic nervous system neoplasm of the pancreatic duct59 bronchial asthma/ attack bronchial asthma 91

Blood plasma serum (Ag/ml)

Urine (^g/24 hr)

Liquor or other fluids of the body (/ig/ml)

burns

renal insufficiency liver cirrhosis traumatic shock

Type tumour métastases

Quantity (Mele)

increased

lung bronchi

increased

0-26-0-37

318

22

565 656

> o

55 21

increased60

increased

increased

increased61 increased slightly increased

infiltrations of the skin increased

exudate of blisters : 1-5

"R f*fί»ι*ί*η C£»Q 1 V U V 1 V11WO

o r o o o > r

increased

>J

>» >» in wool workers eosinophil infiltration of the lung chronic myeloid leukaemia leukaemia

Tissue

10

698 703 703 652 672 700, 934, 1456, 1458 636

H

< >

2 M C/3

Ti

O

c z Ö

421, 688-91, 699 421, 691 421 644 757 655

>

cardiac insufficiency

Imidazole acetic acid

Ribosylimidazole acetic acid 1,4-Methylhistamine 1,4-Methylimidazole acetic acid iV-Methylhistamine N,iV-Dimethylhistamine

thyrotoxicosis hyperthyroidism hypothyroidism chronic atrophie dermatitis mastitis carcinoma of the mamma carcinoma of the lung myotonic dystrophy normal mastocytosis metastasizing carcinoma of unknown origin normal mastocytosis normal mastocytosis normal mastocytosis normal normal

erythr. : increased

647

increased

increased

+

up to 2600 up to 2300

+ + + + + + + +

pleura transudate: 0006001 oedema fluid: 00080013

647

647

skin skin skin

increased decreased increased

281 681 681 756

mamma mamma

increased (increased)

687 687

tumour

decreased

1457 678 635,62 67763 697, 705 705 635,62 67763 635,62 69762 63564 635,64 69764 635,64 677,65 1849 635,64 69764 673 673

CO

3 o X 5ö

<

TABLE 3—continued

Occurrence Normal Pathological

JV-Acetylhistamine

Ethylamine Colamine

normal

/?-Hydroxypropylamine /i-Butylamine Isobutylamine

normal

+ males: 530010300 females : 1990031700

cystinuria normal cystinuria normal

of the body (//g/ml)

Type

Quantity (/*g/g)

menstrual blood: +

64

brain

+

+

see Table 4 (P. 60)

liquor : -0-5-1-5

697 338, 706, 707 708

o r o

O

o > r r >

283 709

O H

338,709-11

>

<

I—I

m c«

brain

breast milk: +

+ + +

References 338, 673

+

normal >>

Isoamylamine

(g/i/24 hr)

+ +

mastocytosis normal normal >>

Tissue

Liquor or

1-108 ßg per mg creatinine

normal

Dimethylaminoethanol

Putrescine Cadaverine

Blood plasma serum 0/g/ml)

placenta66

see Table 4 (p. 60)

+

708, 712 338 713 714 714 715-18 719 715-18 283 721-3

»fl

O C

>

2

1

Using older (less specific) methods. Single observation. 3 "Tumours of the sympathetic nervous system" is generally used in Table 3 as group designation for neuroblastoma, sympathogonioma, ganglioneuroblastoma, ganglioneuroma, etc. 4 Single observation. 5 Occurrence has been made probable. 6 Patients with hypertension. 7 Single observation. 8 Single observation. 9 After giving marked dopa. 10 Among a number of patients. 11 In 8·8-20% of the patients; other authors ( 3 5 9 · 422 -4> with a limited number of patients, under certain experimental conditions (orthostatic test) give a decreased excretion of noradrenaline. 12 With a number of patients ( 4 2 0 ) ; only in the acute stage ( 4 1 9 ) . 13 Single observation. 2

15

In the acute stage.

55

Compared to a control group (9 cholecystectomized patients) with a medium rate of 0-0015 ßg noradrenaline per ml blood of the portal vein; other authors did not find an increase/ 1 4 3 0 ) 16 Compared to strumata with normal function of the thyroid gland. 17 Not differentiated. 18 Circulatory insufficiency. 19 In joint analysis with metanephrine up to 113000 ßg per 24 hr ( 2 0 4 ) . 20 In healthy test subjects after intravenous injection of marked noradrenaline. 21 In 2 3 % of the cases. 22 After intravenous application of marked noradrenaline. 23 Occurrence made probable. 24 Other authors were not able to demonstrate adrenaline in the brain. 25 With a number of patients. 26 Single observations. 27 Compared to a control group (9 cholecystectomized patients) with an average value of 00024ßg adrenaline per ml of portal vein blood. 28 Compared with a normal functioning thyroid gland. 29 In the insulin test compared to the healthy subject. 30 With circulatory insufficiency. 31 In joint analysis with normetanephrine up to 113000 Mg per 24 hr. ( 2 0 4 ) 32 Proved in 4 of 800 examined samples of urine.

BIOCHEMISTRY

14

33

Single observations. In 5 of 8 cases. 35 Single observations. 36 Mucosa. 37 Related to moist weight; the equivalents per gram dry weight are correspondingly higher (see, in addition, ref. 533). 38 Related to dry weight. 39 Related to moist weight. 40 Dissection material of patients with various illnesses not connected with the spleen. 41 Dissection material of patients with various neurological and internal illnesses. 42 Autopsy material. 43 With carcinoid syndrome. 44 With carcinoid syndrome. 45 Occurrence made probable. 46 With carcinoid syndrome. 47 By biological methods. 48 Thrombocyte—serotonin. 49 Single observations. 50 Thrombocyte—serotonin. 51 Thrombocyte—serotonin. 52 With carcinoid syndrome. 53 Bufotenine could be demonstrated in only 9 of 50 examined subjects. 54 Single observations. 55 5-Methoxytryptamine was found in the blood of 4 out of 46 examined subjects. 56 In different parts of the skin of the head 20-30 //g per g of histamine wet weight of tissue was found/ 755) 57 Material from operations and dissections of patients with various internal or neurological illnesses. 58 Material from operations and dissections of patients with various internal or neurological illnesses. 59 With carcinoid syndrome. 60 Single observation. 61 Single observation. 62 After oral application of marked histidine. 63 After intradermal application of marked histamine. 64 After oral application of marked histidine. 65 After intradermal application of marked histamine. 66 Older, autolytically altered placenta.

Os

34

w

g r g ** P r [1 ~ H 5 ra

> S Z ^ ^ O |G § ^ Z g > 2

TABLE 4. AMINES IN THE HUMAN BRAIN*

O

Brain area

Dopamine m Per g tissue

References

147 147, 275

Gyms postcentralis

0-03-0-31

Gyrus frontalis sup. Gyrus frontalis med. Gyrus frontalis inf. Gyrus parietalis sup. Gyrus parietalis inf. Gyrus cinguli Gyrus occipitalis lat. Gyrus temporalis sup. Gyrus temporalis med. Gyrus hippocampi Uncus gyri hippocampi Gyrus dentatus Area olfactoria Insula Capsula interna

011 003 002 007 002

124, 147, 275 147, 275 147, 275 147,275 147, 275 147,275

003-007 008 004-007 004-007

MS Per g tissue

References

0-002

124

0-003; 006 002-004 001 002 002

124,147, 275 124, 147, 275 275 147, 275 147, 275

147, 275 147, 275 147, 275 147, 275

001 004-005 001-005 002-008 001-002 001-008

147,275 147, 275 147, 275 147, 275 147, 275 147,275

0-06-0-16

147,275

001-007

147,275

0-08 | 0-07-1-25

147 147, 275

004 | 004

147 147

Serotonin Mg per g tissue

References

001-004

124, 530

001-003 004 001-007 006 001-006 0-05-0-35

530 531 530 124 124, 530 530

00Φ-01

530

0-1-0-3 0-16-0-30

530 530

0-45-1-51

530

Other amines or metabolites Mg per g tissue

References

55

005 0-13-0-25

Noradrenaline

BIOCHEMISTRY

Frontal brain Frontal lobe Frontal pole Cortex area 4 Temporal pole Occipital lobe Occipital pole Corpus callosum Gyrus praecentralis

|

TABLE 4—continued

oo

Norad renaline

Dopamine Tira in arpa

■Luuiii c u v a

Nucleus caudatus

M% per g References tissue 0-8-6-69

Putamen

2-1-9-43

Claustrum Nucleus amygdalae

0-16-0-67 006-10

Septum pellucidum

0-01-0-3

Hippocampus Fimbria hippocampi Fornix Hypothalamus

013 0-26 0-5-2-23

Pallidum

0-05-1-34

Corpora mammilaria Hypophysis Epiphysis

001-002 0-5

Corpora quadrigemina

0-07-0-4

Colliculis rostralis Colliculis caudalis

124,147, 275, 311-13 124, 147 275,311, 313 124 147, 275, 311 124,147, 275,311 147, 275 275 124, 147, 275,311, 313 124, 147, 275,311, 313 124 147, 275

147, 275, 311 0-07-0-18 124 0-0-15 1 124

Serotonin

Other amines or metabolites References

m Per g tissue

References

MS per g tissue

References

MZ per g tissue

0-02-2-8

124,147, 275, 311-13 124, 147, 275,311, 313 124 147, 275, 311 124, 147, 275,311

0-20-0-70

124, 313, 530

homovanillic acid: 3-38

1845

0-30-0-95

124, 313, 530

homovanillic acid: 4-47

1845

0-14-0-67

530

003

124

005-019

530,531

0-06-0-55 0-16-1-53

530 124, 312, 313, 530

0-08-0-73

124, 313, 530

0-27-0-48

530

0-36-22-82 (3-28)

541

0-50-1-02 0-29-0-81

530

002-014 0-007 0-03-0-24 0-03-0-37

147, 275 275 124, 147, 275,311, 313 124, 147, 311,313

004 007 0-31-1-78 0-02-1-8

01

147, 275

0-11-0-23

147, 275, 311 124

007-018 0-06-0-33

1

124

530

o r o

O

o > r r > o

H

<

a

>

5

w

►a

homovanillic acid: 2-25

1845

o c

2

>

1

0-5 1 008-1-46

Zona compacta Zona reticulata Nucleus ruber

0-62-0-89 0-01-0-60 0-12-1-52

Thalamus Thalamus rostralis

0-2-0-4 002-016

Thalamus medialis

0-03-0-74

Thalamus lateralis

0-0-52

Cerebellum Cortex cerebelli Monticulus Nucleus dentatus

001-002 003-005 003-008

Basis pedunculi Oliva Nucleus olivae Pyramis Formatio reticularis Medulla oblongata

002 0-04-0-11 0-4-0-8 016-018 0-3-0-6 0-04-0-30

Area postrema Pons

1-3 0-2

124 124, 275 124, 147, 275,311 124 147, 275 311 147, 275 313,314 124,147, 275 311 311

Pons ventr. Pons dors. Brachium pontis Unspecified areas

002-015 0-08-0-24 0-11-0-47

147, 275 147, 275 147

313 124,147, 275,311, 313, 314 314 314 124, 147, 275,311 311,313 124, 147, 275 124, 147, " 275,311 124,147, 275

0-53 124, 147, 0-55-1-96 275,311,| 313,313

313

313 313, 530

homovanillic acid: 2-32

1845

Adrenaline 00044

269

314

314 124,147, 275,311 311,313 124, 147

0-26-2-70

313, 530

147, 275, 311 147, 275

0-13-0-35

124

0-13-0-30

124

147 147 147 124, 147, 311

001-009

530

0-60 0-20-0-50

313 124, 530

0-43-0-81 019-103

530 124, 530

147, 275 311 147 311,313 124,147, 275 311 124, 147, 311 275 147, 275 147, 275 269

BIOCHEMISTRY

Central grey matter Substantia nigra

55

TABLE 4—continued

Brain area

Unspecified areas

Dopamine Mg per g tissue

References

Noradrenaline Më per g tissue

References

Serotonin Mg per g tissue

References

Other amines or metabolites Mg per g tissue Histamine 0-26-0-37 ethylamine + Diaminoethanol 00051 3,4-dihydroxyphenylacetic acid 009

References 318 708 708, 712 269, 312

O

r o O o >

> o H

< >

2 m

* Dissection material from patients with various diseases or after death from various causes (myocardial infarction, cerebral arterio­ O sclerosis, neoplasma, leukaemia, strangulation, etc.). Ö

2

TABLE 5. AMINES IN THE HUMAN SPINAL CORD AND IN PERIPHERICAL NERVES

Spinal cord Spinal nerves Vegetative nerves

Dopamine μ% per g tissue

References

0-24-0-41

272

Noradrenaline

Adrenaline

Histamine

Mg per g References tissue

MS Per g References tissue

Me Per g References tissue

007-018

272*

1-3

386

-4-5

469

-2-10

686

Melatonin μ% per g tissue

References

+

645

BIOCHEMISTRY

Localization

* Specified as noradrenaline, but may be a mixture of noradrenaline+adrenaline.

55 O

ON T A B L E 6. PROPORTIONS OF D O P AMINE, N O R A D R E N A L I N E A N D S E R O T O N I N I N THE H U M A N B R A I N I N P A R K I N S O N ' S D I S E A S E

Amine

Dopamine

Noradrenaline

Serotonin

Brain area

nucleus caudatus putamen pallidum thalamus hypothalamus substantia nigra nucleus caudatus putamen pallidum thalamus hypothalamus substantia nigra nucleus caudatus putamen pallidum thalamus hypothalamus substantia nigra

Normal

M. Parkinson

//g amine per g brain tissue

μ% amine per g brain tissue

3-5 3-7 0-5 0-3 0-8 0-46-0-9 009 012 015 013 1-25 004 0-33 0-32 0-23 0-26 0-29 0-55

1-1; 0-2* 0-8; 0-3* 0-3; 0 1

— —

007 008; 002* 007; 003* 006; 0-23



0-98 002 0-12 0-14 013 013 0-12 0-26

References

o r o

O

311 311 311 311 311 311,314 311 311 311 311 311 314 531 531 531 531 531 531

o > < > o H

< a

>

S m c/a *ïl

O C

O

>

z '· Postencephalitic Parkinsonism.