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Urinary metabolites of aromatic amino acids in schizophrenia
Life Sciences No . 2, pp . 61-64, 1962 " Britain .
Pergamon Press Ltd .
Printed in Great
URINARY METABOLITES OF AROMATIC AMINO ACIDS IN SCHIZOPHRENIA Michael H . Briggs and Natalie Harvey Victoria University of Wellington, New Zealand (Received g January 1962j Tf~RS have been a nimber ~ reports that the urine of schisophx~enics contains unusual aromatio com~peunda not Pound in normal urine, nor in that from other psychotica . i-5 Moreover, one group ad waa~kers~ have offered evidence that these unusual metabolites are derived from dietary pher~rlalanine and tyrosine and can be eliminated from schizophrenics " urine by feeding a diet low in these two amino acids.
This evidence can be ezplaiaed if there is an
impairnient in schizophrenics of the phenTplalanine aQidase system .
In
other work6 ' 7 evidence has been pa~esented for an excessive breakdam of ascorbic acid in schizophrenics .
Nos ascorbic acid is an activator of orge
enzyme of the phenylalanine oxidase system, ~-hydro~pher~ylpyruvate aad.daae .8 Consequently, the obsertrations of the pa"evious worlrors could be ezplained by a partial inhibition of this enzyme in the tissues aâ schizophrenics . To examine this hypothesis we have compared the ara®atic metabolites gresent in schizophrenics' urine with those in urine from a na~rmal group and from a group of non-schizophrenic psychotics .
We have looked particularly
for the pa"esenee and absence of the taro compounds knosn to be excreted. during the inhibition of ~-hydroxypher~ylpyruvate ox;.dase :
~hydroxyphenylpyzuvats
and ~-hydrozyphenyllactate . 8 Clinical details of the patients investigated are given in Table 1 . Diagnosis of schizophrenia was based on clinical evidence of hallucinations ; grandiose, persecution and other delusions ; excitement .
withdrawal and periodic
Both groups of patients included highly active, inactive and
subjects oaf variable activity.
All groups received a normal mixed diet 61
URINA;tY METABOLITES
6Z which included fresh fruits .
iJ~, .
PIo estimate of the amounts of ascorbate and
aromatic amino acids in the diets was made, but both groups of patients received identical foods and the non-schizophrenics thus form a control group for the schizophrenics for these factors .
Measurements of total
urinary excretion of ascorbate and its major metabolites (dehy~7roascorbate and diketogulonate) gave similar results for each group.
This provides adr3itional
evidence for e similar, and adequate, dietary supply of the vitamin for all subjects . TARIE 1 Clinical Details of Patients and Subjects
Group
No .
Schizophrenic Patients
15
:~on-schizophrenic Patients
12
Normal Subjects
Diagnosis 10 paranoid 5 simple
Age (yrs .) Range Mean x-52
6 depuressives 1 senile mania state 1 paraphrenic 3x72 2 manic depressive 1 psychopathic pe rs onality 1 alcoholic
18
20-58
-
Duration of Tllness (yra . Range Mean
ßody Wt . (lbs .) Range Mean
1,0
2-35
12
121+-196 162
~
1-35
7
1 26-178 156
38
-
135-185
165
TJrine fran 15 male schizophrenics, 12 male non-schizophrenic psychotics, and 18 normal males was submitted to paper chromatography .
experiments have
been conducted with untreated urine s, concentrated urines, and. with ether extracted urines .
Solvents used were chloroform-acetic acid-water and 20;
potassium chloride solution .
Compounds were detected by first examining the
chromato rams wider an ultra-violet lamp, then by spraying freshly diazotized sulphanilic acid, followed by sodium carbonate solution . Results are summarized in Table 2. 3ooth et a1 . 9
~, values are those established by
No .2
63
URINARY METABOLITES TABLE 2 Aromatic Amino Acid metabolites in Urine
Rf Metabolite
1
No . of subjects in which detected
2
Normal subjects (18)
Schizophrenic patients
(15)
Non-schizophrenic patients (12)
0,13
0,90
5
15
4
~hydroxypher~yllactate
0 .11
0 .76
3
12
4
~hydro~rphe~lacetate
0,1,1 .
0,78
13
14
12
p-hydroxypheruylpyruvate
solvent 1 - chloroform-acetic acid-water solvent 2 - ~ KC1 solution
These results clearly indicate an abnormality in the metabolism of tyrosine in schizophrenics .
Other aromtic compounds that have not yet been identified
also were poresent only in schizophrenics' urine. The most likely explanation of the metabolic abnormality in schizop~hrenica is a partial inhibition of ~-hydraarypheruylpyruvate axidase due to sub-optimum amounts A of ascorbate. 7
blockage oP the phetiplalanine oxidase system at a
different level occurs in another mental disorder, phcnylpyruvic oligophrenia . l0 The mental defect in both cases could be caused by a toxic effect of the circulatir~ aromatic metabolites, or by an imbalance in aromatic transformations, Thus an increased synthesis of epinephrine from dihydroxypheu>,glelanine would be a likely result a~f impaired oxidation of tyrosine .
There is knave to be
increased tissue epinephrine in scurvy, ll and there is experimental evidence a~P l2-13 Excessepinephrine abnormal epinephrine metabolism in schizophrenics . cail.d be metabolised to assns compound having psychotomimetic properties, such as adrenochrame, adrenolutin, ar other metabolite bearing a structural resemblance to riescaline our related hallucinogen .
Acknowled.Rement - We are grateful for the assistance of Dr . B.D . Hart and his staff the Porirua Hospital .
64
URINARY METABOLITES References
1.
b~ . K. YOUNG, JR ., Univ . Texas Pibl . No . 5109, 189 (1951) .
2.
I. SANO, Folie Psychiat . Neurol . Japan =$, 218 (1954) "
3.
P. L. Mcf~R, B . G . kcGEEit aryl gf. C . GIHSON, Science ~, 1029 (1956 )
1{..
P. L. MoGEER, $ . G. Md~R and Yl . C . GIRSON, Sc ience ~, 1078 (1956 ) .
5.
P. L. McK~ER, F . S . McNAIR, E . G . NrcC~R anä. 1P . C . GIBSCMI, J. t?erv. Ment . Dis. ~, 1 and 11
(1957) "
6.
G . B. KITTO, E . D . AI~RBRS and I~ . H . BRIGGS, to be published (1962) .
7.
M. H. ~tIGGS, N.Z . Med. J . in press (1962) .
8.
B . N . La DUE and V. G . ZAN1~'ONl, Ann . N.Y . Aced . Sci . ~2, 175 (1961) "
9.
A. N. HOO~i, l~. S . I~ASRI, D . J. ROBBINS, 0 . A. Sb~RSON, F. T . JODS and F. De SDS, J . Bio1 . Chem . 2~, 2649 (1960) .
10 .
C . MI1'~f.A, R . M . AUID and H . UDENFRIEI~, Pros . Soc. Exptl. 3io1 . bled.
.24, 634 (1957) . 11 .
A. GIE20~ and M. MARTIT~T, Bu1L Sac . Chien. Biol . ~, 456 (1941 ) .
12 .
J . R . S~THIES, Lancet ü, 308 (1958) "
13 .
1, 108 H. SUIKO9VITCH and M . D. ALTSCf?UIE, A .M .A . Arch . Gen. F~ychiat . 3
No .z
Pergamon Press Ltd .
Printed in Great
URINARY METABOLITES OF AROMATIC AMINO ACIDS IN SCHIZOPHRENIA Michael H . Briggs and Natalie Harvey Victoria University of Wellington, New Zealand (Received g January 1962j Tf~RS have been a nimber ~ reports that the urine of schisophx~enics contains unusual aromatio com~peunda not Pound in normal urine, nor in that from other psychotica . i-5 Moreover, one group ad waa~kers~ have offered evidence that these unusual metabolites are derived from dietary pher~rlalanine and tyrosine and can be eliminated from schizophrenics " urine by feeding a diet low in these two amino acids.
This evidence can be ezplaiaed if there is an
impairnient in schizophrenics of the phenTplalanine aQidase system .
In
other work6 ' 7 evidence has been pa~esented for an excessive breakdam of ascorbic acid in schizophrenics .
Nos ascorbic acid is an activator of orge
enzyme of the phenylalanine oxidase system, ~-hydro~pher~ylpyruvate aad.daae .8 Consequently, the obsertrations of the pa"evious worlrors could be ezplained by a partial inhibition of this enzyme in the tissues aâ schizophrenics . To examine this hypothesis we have compared the ara®atic metabolites gresent in schizophrenics' urine with those in urine from a na~rmal group and from a group of non-schizophrenic psychotics .
We have looked particularly
for the pa"esenee and absence of the taro compounds knosn to be excreted. during the inhibition of ~-hydroxypher~ylpyruvate ox;.dase :
~hydroxyphenylpyzuvats
and ~-hydrozyphenyllactate . 8 Clinical details of the patients investigated are given in Table 1 . Diagnosis of schizophrenia was based on clinical evidence of hallucinations ; grandiose, persecution and other delusions ; excitement .
withdrawal and periodic
Both groups of patients included highly active, inactive and
subjects oaf variable activity.
All groups received a normal mixed diet 61
URINA;tY METABOLITES
6Z which included fresh fruits .
iJ~, .
PIo estimate of the amounts of ascorbate and
aromatic amino acids in the diets was made, but both groups of patients received identical foods and the non-schizophrenics thus form a control group for the schizophrenics for these factors .
Measurements of total
urinary excretion of ascorbate and its major metabolites (dehy~7roascorbate and diketogulonate) gave similar results for each group.
This provides adr3itional
evidence for e similar, and adequate, dietary supply of the vitamin for all subjects . TARIE 1 Clinical Details of Patients and Subjects
Group
No .
Schizophrenic Patients
15
:~on-schizophrenic Patients
12
Normal Subjects
Diagnosis 10 paranoid 5 simple
Age (yrs .) Range Mean x-52
6 depuressives 1 senile mania state 1 paraphrenic 3x72 2 manic depressive 1 psychopathic pe rs onality 1 alcoholic
18
20-58
-
Duration of Tllness (yra . Range Mean
ßody Wt . (lbs .) Range Mean
1,0
2-35
12
121+-196 162
~
1-35
7
1 26-178 156
38
-
135-185
165
TJrine fran 15 male schizophrenics, 12 male non-schizophrenic psychotics, and 18 normal males was submitted to paper chromatography .
experiments have
been conducted with untreated urine s, concentrated urines, and. with ether extracted urines .
Solvents used were chloroform-acetic acid-water and 20;
potassium chloride solution .
Compounds were detected by first examining the
chromato rams wider an ultra-violet lamp, then by spraying freshly diazotized sulphanilic acid, followed by sodium carbonate solution . Results are summarized in Table 2. 3ooth et a1 . 9
~, values are those established by
No .2
63
URINARY METABOLITES TABLE 2 Aromatic Amino Acid metabolites in Urine
Rf Metabolite
1
No . of subjects in which detected
2
Normal subjects (18)
Schizophrenic patients
(15)
Non-schizophrenic patients (12)
0,13
0,90
5
15
4
~hydroxypher~yllactate
0 .11
0 .76
3
12
4
~hydro~rphe~lacetate
0,1,1 .
0,78
13
14
12
p-hydroxypheruylpyruvate
solvent 1 - chloroform-acetic acid-water solvent 2 - ~ KC1 solution
These results clearly indicate an abnormality in the metabolism of tyrosine in schizophrenics .
Other aromtic compounds that have not yet been identified
also were poresent only in schizophrenics' urine. The most likely explanation of the metabolic abnormality in schizop~hrenica is a partial inhibition of ~-hydraarypheruylpyruvate axidase due to sub-optimum amounts A of ascorbate. 7
blockage oP the phetiplalanine oxidase system at a
different level occurs in another mental disorder, phcnylpyruvic oligophrenia . l0 The mental defect in both cases could be caused by a toxic effect of the circulatir~ aromatic metabolites, or by an imbalance in aromatic transformations, Thus an increased synthesis of epinephrine from dihydroxypheu>,glelanine would be a likely result a~f impaired oxidation of tyrosine .
There is knave to be
increased tissue epinephrine in scurvy, ll and there is experimental evidence a~P l2-13 Excessepinephrine abnormal epinephrine metabolism in schizophrenics . cail.d be metabolised to assns compound having psychotomimetic properties, such as adrenochrame, adrenolutin, ar other metabolite bearing a structural resemblance to riescaline our related hallucinogen .
Acknowled.Rement - We are grateful for the assistance of Dr . B.D . Hart and his staff the Porirua Hospital .
64
URINARY METABOLITES References
1.
b~ . K. YOUNG, JR ., Univ . Texas Pibl . No . 5109, 189 (1951) .
2.
I. SANO, Folie Psychiat . Neurol . Japan =$, 218 (1954) "
3.
P. L. Mcf~R, B . G . kcGEEit aryl gf. C . GIHSON, Science ~, 1029 (1956 )
1{..
P. L. MoGEER, $ . G. Md~R and Yl . C . GIRSON, Sc ience ~, 1078 (1956 ) .
5.
P. L. McK~ER, F . S . McNAIR, E . G . NrcC~R anä. 1P . C . GIBSCMI, J. t?erv. Ment . Dis. ~, 1 and 11
(1957) "
6.
G . B. KITTO, E . D . AI~RBRS and I~ . H . BRIGGS, to be published (1962) .
7.
M. H. ~tIGGS, N.Z . Med. J . in press (1962) .
8.
B . N . La DUE and V. G . ZAN1~'ONl, Ann . N.Y . Aced . Sci . ~2, 175 (1961) "
9.
A. N. HOO~i, l~. S . I~ASRI, D . J. ROBBINS, 0 . A. Sb~RSON, F. T . JODS and F. De SDS, J . Bio1 . Chem . 2~, 2649 (1960) .
10 .
C . MI1'~f.A, R . M . AUID and H . UDENFRIEI~, Pros . Soc. Exptl. 3io1 . bled.
.24, 634 (1957) . 11 .
A. GIE20~ and M. MARTIT~T, Bu1L Sac . Chien. Biol . ~, 456 (1941 ) .
12 .
J . R . S~THIES, Lancet ü, 308 (1958) "
13 .
1, 108 H. SUIKO9VITCH and M . D. ALTSCf?UIE, A .M .A . Arch . Gen. F~ychiat . 3
No .z