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A genetic study of platelet phenolsulphotransferase activity in normal and schizophrenic twins
J. psychiaf. Res., Vol. 17, No. 3, pp. 303-307. Printed in Great Britain.
0022-3956/83 0 1983 Pergamon
1982183.
$3.00+.00 Press Ltd.
A GENETIC STUDY OF PLATELET PHENOLSULPHOTRANSFERASE ACTIVITY IN NORMAL AND SCHIZOPHRENIC TWINS ADRIANNE M. REvELEY,*t
SUSAN M. BONHAMCARTER,+ MICHAEL A. REvELEYt and MERTON SANDLER*
j-Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.; *Bernhard Baron Memorial Research Laboratories, Queen Charlotte’s Maternity Hospital, London W6 OXG, U.K. (Received Summary-In the enzyme, Both were between 11 and 12 male
11February 1983; revised21 April 1983; receivedforpublicarion
23 June 1983)
a series of 19 identical and 16 fraternal twin pairs, the activities of the two forms of phenolsulphotransferase, denominated M and P, were investigated in blood platelets. shown to be under a high degree of genetic control. No differences were found schizophrenic patients from discordant twin pairs, compared with their well cotwins and female volunteer twin pairs, for either form of the enzyme. INTRODUCTION
BIOLOGICAL markers of the major psychoses are difficult to pinpoint. Despite some tantalizing clues, few hard biochemical differences between normal and schizophrenic patients have stood up to prolonged scrutiny. Even with the persistence of the dopamine hypothesis, all claims to have identified changes in this system have been hard to replicate. One constant difficulty has been in access to enzyme systems which might be distorted by the disease process and the only practicable approach has been to focus, in general, on the formed elements of the blood and, in particular, on the blood platelets. One such platelet enzyme with overtones of the dopamine hypothesis, which has been particularly well studied in schizophrenia (though with equivocal results), is monoamine oxidase (MAO) B. We now present our investigations into the status of another monoamine-degrading enzyme found in the blood platelet, phenolsulphotransferase (PST), in a series of normal and schizophrenic twins.
Sulphoconjugation by PST is an important but relatively under-studied pathway for the metabolism of a wide variety of substrates, including monoamines, their metabolites and many phenolic drugs (SANDLERand USD~N, 1981). It is a soluble enzyme, widely distributed in the body and, within the context of this particular paper, having substantial activity in platelets (HART et al., 1979; ANDERSON and WEINSHILBOUM, 1980; REINef al., 1981) and it is also distributed discontinuously in the brain, although it may play a less important metabolic role in this tissue than MAO (ROTH et al., 1982). Recently two forms, PST M and PST P, active respectively against monoamines and phenol at low concentration, have been identified in human tissues (REIN et al., 1982) and shown to be under separate control (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). *To whom correspondence
and reprint requests
should be addressed 303
304
A. M. REVELEY
et
al
The possibility exists that altered PST activity is of functional importance in schizophrenia, either by direct involvement in its pathogenesis, or by modifying the response to certain drugs. To date, there have been no studies of platelet PST activity in schizophrenics. Little enough is known about the enzyme itself in the normal state; in particular, no information is available of the degree of genetic control of its activity. We have, therefore, taken advantage of an ongoing study of schizophrenic twins to investigate both these aspects of PST activity. METHODS Eleven schizophrenic patients, identified from the Maudsley Hospital Twin Register, who had a well, non-schizophrenic cotwin, participated in the study. The diagnosis of schizophrenia was confirmed after semi-structured interview (SPITZER and ENDICOTT, 1977) using the Research Diagnostic Criteria of SPITZER et al. (1975). Nine patients had schizophrenia, chronic course, and two had had schizophrenic episodes with incomplete recovery. Ten had chronically taken a variety of neuroleptic agents including seven on depot preparations, while one (a severely withdrawn schizoid individual) was maintained without neuroleptics. None of the well cotwins that we tested (seven from MZ pairs and one from a DZ pair) were taking or had ever taken neuroleptic agents. Twenty-seven pairs of twins from the Institute of Psychiatry Volunteer Twin Register also agreed to participate. Zygosity had been assessed, in all cases, by direct physical comparison and blood group determination in at least eleven systems. Twenty millilitres of venous blood was taken from each subject by venepuncture and placed in plastic Universal containers with 0.5 ml of 5% NaEDTA. A 10 ml aliquot was centrifuged at 320 g for 5 min at 20°C to obtain platelet rich plasma which was then centrifuged at 4300 g for 20 min at 20°C. The platelet pellet was resuspended and washed in 1 ml of 0.32 M sucrose, vortex-mixed, and again centrifuged at 4300 g for 20 min at 20°C. The platelet pellet was stored at -20°C until assay when it was resuspended in 1 ml sucrose (0.32 M). Aliquots from all subjects were then coded and sent in two batches for PST estimation according to the method outlined by BONHAM CARTER et a/. (1981), using p-tyramine at a final concentration of 75 FM as PST M substrate and phenol at a final concentration of 30pM as PST P substrate. The assay was performed blind to psychiatric status and zygosity. Results were analyzed using the two-tailed Student’s f statistic, the twin (intraclass) correlation ‘r’ (EMERY, 1976) and F ratios according to the method of OSBORNE et al. (1959). RESULTS For neither form of the enzyme, PST M nor PST P, were differences found between the eleven schizophrenics, their eight non-medicated cotwins or any of the control groups (Table 1). Our subjects did not differ in mean age and, in common with previous work, there did not appear to be any effect of sex on PST activity (BONHAM CARTER er al., 1981) or any correlation between the individual PST M and P activities in the group as a whole (r= 0.10) (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). We therefore decided to combine all the twin groups to estimate the genetic contribution to enzyme activity.
PLATELETPHENOLSULPHOTRANSFERASE ACTIVITY IN TWINS TABLE
1. PLATELET PST
305
ACTIVITIESIN SCHIZOPHRENICSAND CONTROLS(NMOL PRODUCT FORMED/W PROTEIN/IO MIN INCUBATION; MEAN k SEM)
Age Group
N
(mean k SEM)
Discordant schizophrenic twins Schizophrenics MZ MZandDZ Well co-twins MZ MZandDZ
I 11 7 8
38.0 f 4.2 40.3 + 3.9 38.024.2 38.2 k 3.6
0.34 0.34 0.36 0.35
f 0.03 zk 0.03 k 0.04 f 0.04
0.07 0.07 0.08 0.08
* f k +
0.02 0.01 0.02 0.01
12 14 12 16
37.9 37.6 40.0 40.4
0.37 0.36 0.32 0.35
f 0.03 -+ 0.02 ” 0.02 -c 0.02
0.07 0.09 0.09 0.08
f + + f
0.01 0.01 0.01 0.01
Controls Females
MZ DZ MZ DZ
Males
k f It 2
PST-M
4.6 5.0 4.9 3.5
PST-P
Demonstration of a genetic effect depends on finding significantly greater similarity between members of monozygotic (MZ) twin pairs than among dizygotic (DZ) twin pairs. MZ twins always share 100% of their genes, while DZ twins share an average of 50%, though the individual members of a given DZ pair may share anything from 0 to 100% of the genes influencing a particular trait, depending on the chance assortment of genes at conception. In addition, the sensitivity and accuracy of the experimental measurement of the trait must be sufficient to demonstrate the similarity of the twin pairs compared with the range of variation in the sample as a whole. It will be seen from Table 2 that the MZ twins are significantly more alike than the DZ twins both for PST M and PST P. Table 3 shows that interpair variances, which reflect the range of variation in enzyme activity in each twin group, are quite similar for MZ and DZ twins, for each form of the enzyme. The twin intraclass correlation r, calculated by the formula ,_leIa, Ze + Ia where Ze and laare interpair and intrapair variances respectively, shows the correlation values for each twin pair against the background of total variation in the sample, and significance can be tested by comparing the F ratio of Ze/Za. Table 3 shows that MZ twins are significantly correlated for PST M, while DZ twins not. For PST P, both groups show significant correlations, though this is greater for TABLE 2. INTRAPAIR DIFFERENCES IN ENZYME ACTIVITY: MZ vs DZ Twin
Intrapair difference*
Intrapair variance
Fratio
P
0.00132 0.00390
2.96
0.025
0.00033 0.00127
3.85
0.01
PST M MZ (N= 19) DZ (N= 16)
0.042 + 0.01 0.071 f 0.01
MZ (N= 19) DZ (N= 16)
0.019 f 0.004 0.036 f 0.01
PST P
*Mean + SEM.
of its are the
A. M. REVELEY
306 TABLE Twin
group
D.F.
3.THE
GENETIC
el
al.
CONTRIBUTION
Variance
TO
PST ACTIVITY
Twin correlation ‘r’
F ratio
P
MZ
Intrapair Interpair
19 18
PST M 0.00132 0.00758
0.70
5.75
0.001
DZ
Intrapair Interpair
16 15
0.00390 0.00632
0.24
1.62
ns
MZ
lntrapair Interpair
19 18
PST P 0.00033 0.00353
0.83
10.563
0.001
DZ
Intrapair Interpair
16 15
0.00127 0.00367
0.48
2.887
0.025
MZ twins. Eliminating the seven MZ and one DZ schizophrenic pairs from the analyses did not affect the results (for PST P rMZwas 0.85 and rDZ0.24; for PST M rMZwas 0.88 and rDZ 0.44). The twin correlation can be directly interpreted as the proportion of variance roughly attributable to genetic factors, or “heritability” of the trait. Such an interpretation must be an oversimplification of the genetic and environmental influences and interrelationships that underlie the enzyme activity; for example, it takes no account of shared environment, dominance effects or gene-environment interaction. Nevertheless, we believe it to be a useful shorthand estimate. For MZ twins the correlation can be used directly, expressed as a percentage; for DZ twins it must first be doubled to account for the fact that DZ pairs can only be expected to share half their genes. Both estimates should be roughly comparable but, of course, there is no means of knowing exactly what percentage of the genetic constitution for either form of PST activity is shared by this particular group of DZ twins, so the DZ estimates are likely to be less accurate than those for the MZ twins. Thus for PST M, this rough heritability is 70% based on the MZ twins and 48% based on the DZs and for PST P, heritability is 83% based on the MZs and 96% based on the DZ pairs. DISCUSSION Both platelet PST M and PST P activities appear to be under a high degree of genetic control and the lack of correlation between the individual PST M and P activities confirms previous findings that control of these enzymes is separate (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). The genetic contribution appears slightly more marked, and is somewhat more consistent across MZ and DZ groups, for PST P activity. This finding suggests that there is greater environmental influence on PST M activity, which could either be introduced by factors operating in vivo on the twins themselves, e.g. diet, or by greater variation in the assay procedure. Even so (admittedly, the argument is somewhat circular), our finding of a significant genetic effect validates the experimental method used to monitor the trait. Our group of eleven schizophrenics is far too small to form the basis for a confident assertion that altered platelet PST activity is not implicated in the pathogenesis of
PLATELETPHENOLSULPHOTRANSFERSEACTIVITY IN TWINS
307
schizophrenia. The possibility remains that in a larger series a subgroup with altered platelet PST activity might be distinguished. Our demonstration that both forms of the enzyme are under a substantial degree of genetic control will allow future studies to proceed with greater confidence. Acknowledgements-We would like to thank themselves for their help.
Dr Ruth Sanger,
FRS for blood grouping
the twins, and the twins
REFERENCES ANDERSON, R. J. and WEINSHILBOUM, R. M. (1980) Phenolsulphotransferase in human tissue: radiochemical enzymatic assay and biochemical properties. C/in. Chim. Acta 103,79-90. BONHAM CARTER, S. M., CLOVER, V., SANDLER, M., GILLMAN, P. K. and BRIDGES, P. K. (1981) Human platelet phenolsulphotransferase: separate control of the two forms and activity range in depressive illesss. Cfin. Chim. Acfa 117,333-344. BONHAM CARTER, S. M., REIN, G., GLOVER, V., SANDLER, M. and CALDWELL, J. (1983) Human platelet phenolsulphotransferase M and P: substrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide. Er. J. clin. Pharmacol. 15,323-330. EMERY, E. H. (1976) Mefhodology in Medical Genetics, pp. 85-87. Churchill Livingstone, Edinburgh. HART, R. F., RENSKERS, K. J., NELSON, E. B. and ROTH, J. A. (1979) Localisation and characterisation of phenolsulfotransferase in human platelets. Life Sci. 24, 125-130. MWALUKO, G. and WEINSHILBOUM, R. (1982) a-Methyldopa, a-methyldopamine and a-methylnoradrenaline: substrates for the thermolabile form of human platelet phenolsulphotransferase. Br. J. c/in. Pharmacol. 14, 231-239. OSBORNE, R. H., ALDERSBERG, M. D., DE GEORGE, F. U. and WANG, C. (1959) Serum lipids, heredity and environment. A study of adult twins. Am. J. Med. 26,54-59. REIN, G., GLOVER, V. and SANDLER, M. (1981) Sulphate conjugation of biologically active monoamines and their metabolites by human platelet phenolsulphotransferase. Clin. Chim. Acfa 111,247-256. REIN, G., GLOVER, V. and SANDLER, M. (1982) Multiple forms of phenolsulphotransferase in human tissues: selective inhibition by dichloronitrophenol. Biochem. Pharmacol. 31, 1893-1897. ROTH, J. A., RIVETT, A. J. and RENSKERS, K. J. (1982) Properties of human brain phenolsulfotransferase and its role in the inactivation of catecholamine neurotransmitters. In Sulfufe Metabolism and Sulfate Conjugation (Edited by MULDER, G. I., CALDWELL, J., VAN KEMPEN, G. M. J. and VONK, R. J.), pp. 107-114. Taylor & Francis, London. SANDLER, M. and USDIN, E. (Editors) (1981) Phenolsulfotransferase in Mental Health Research. Macmillan, London. SPITZER, R. L. and ENDICOTT, J. (1977) The Schedule for Affective Disorders and Schizophrenia, Liferime Version, 3rd edn. New York State Psychiatric Institute, New York. SPITZER, R. L., ENDICOTT, J. and ROBINS, E. (1975) Research Diagnostic Criteria Instrument No. 58. New York State Psychiatric Institute, New York.
0022-3956/83 0 1983 Pergamon
1982183.
$3.00+.00 Press Ltd.
A GENETIC STUDY OF PLATELET PHENOLSULPHOTRANSFERASE ACTIVITY IN NORMAL AND SCHIZOPHRENIC TWINS ADRIANNE M. REvELEY,*t
SUSAN M. BONHAMCARTER,+ MICHAEL A. REvELEYt and MERTON SANDLER*
j-Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.; *Bernhard Baron Memorial Research Laboratories, Queen Charlotte’s Maternity Hospital, London W6 OXG, U.K. (Received Summary-In the enzyme, Both were between 11 and 12 male
11February 1983; revised21 April 1983; receivedforpublicarion
23 June 1983)
a series of 19 identical and 16 fraternal twin pairs, the activities of the two forms of phenolsulphotransferase, denominated M and P, were investigated in blood platelets. shown to be under a high degree of genetic control. No differences were found schizophrenic patients from discordant twin pairs, compared with their well cotwins and female volunteer twin pairs, for either form of the enzyme. INTRODUCTION
BIOLOGICAL markers of the major psychoses are difficult to pinpoint. Despite some tantalizing clues, few hard biochemical differences between normal and schizophrenic patients have stood up to prolonged scrutiny. Even with the persistence of the dopamine hypothesis, all claims to have identified changes in this system have been hard to replicate. One constant difficulty has been in access to enzyme systems which might be distorted by the disease process and the only practicable approach has been to focus, in general, on the formed elements of the blood and, in particular, on the blood platelets. One such platelet enzyme with overtones of the dopamine hypothesis, which has been particularly well studied in schizophrenia (though with equivocal results), is monoamine oxidase (MAO) B. We now present our investigations into the status of another monoamine-degrading enzyme found in the blood platelet, phenolsulphotransferase (PST), in a series of normal and schizophrenic twins.
Sulphoconjugation by PST is an important but relatively under-studied pathway for the metabolism of a wide variety of substrates, including monoamines, their metabolites and many phenolic drugs (SANDLERand USD~N, 1981). It is a soluble enzyme, widely distributed in the body and, within the context of this particular paper, having substantial activity in platelets (HART et al., 1979; ANDERSON and WEINSHILBOUM, 1980; REINef al., 1981) and it is also distributed discontinuously in the brain, although it may play a less important metabolic role in this tissue than MAO (ROTH et al., 1982). Recently two forms, PST M and PST P, active respectively against monoamines and phenol at low concentration, have been identified in human tissues (REIN et al., 1982) and shown to be under separate control (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). *To whom correspondence
and reprint requests
should be addressed 303
304
A. M. REVELEY
et
al
The possibility exists that altered PST activity is of functional importance in schizophrenia, either by direct involvement in its pathogenesis, or by modifying the response to certain drugs. To date, there have been no studies of platelet PST activity in schizophrenics. Little enough is known about the enzyme itself in the normal state; in particular, no information is available of the degree of genetic control of its activity. We have, therefore, taken advantage of an ongoing study of schizophrenic twins to investigate both these aspects of PST activity. METHODS Eleven schizophrenic patients, identified from the Maudsley Hospital Twin Register, who had a well, non-schizophrenic cotwin, participated in the study. The diagnosis of schizophrenia was confirmed after semi-structured interview (SPITZER and ENDICOTT, 1977) using the Research Diagnostic Criteria of SPITZER et al. (1975). Nine patients had schizophrenia, chronic course, and two had had schizophrenic episodes with incomplete recovery. Ten had chronically taken a variety of neuroleptic agents including seven on depot preparations, while one (a severely withdrawn schizoid individual) was maintained without neuroleptics. None of the well cotwins that we tested (seven from MZ pairs and one from a DZ pair) were taking or had ever taken neuroleptic agents. Twenty-seven pairs of twins from the Institute of Psychiatry Volunteer Twin Register also agreed to participate. Zygosity had been assessed, in all cases, by direct physical comparison and blood group determination in at least eleven systems. Twenty millilitres of venous blood was taken from each subject by venepuncture and placed in plastic Universal containers with 0.5 ml of 5% NaEDTA. A 10 ml aliquot was centrifuged at 320 g for 5 min at 20°C to obtain platelet rich plasma which was then centrifuged at 4300 g for 20 min at 20°C. The platelet pellet was resuspended and washed in 1 ml of 0.32 M sucrose, vortex-mixed, and again centrifuged at 4300 g for 20 min at 20°C. The platelet pellet was stored at -20°C until assay when it was resuspended in 1 ml sucrose (0.32 M). Aliquots from all subjects were then coded and sent in two batches for PST estimation according to the method outlined by BONHAM CARTER et a/. (1981), using p-tyramine at a final concentration of 75 FM as PST M substrate and phenol at a final concentration of 30pM as PST P substrate. The assay was performed blind to psychiatric status and zygosity. Results were analyzed using the two-tailed Student’s f statistic, the twin (intraclass) correlation ‘r’ (EMERY, 1976) and F ratios according to the method of OSBORNE et al. (1959). RESULTS For neither form of the enzyme, PST M nor PST P, were differences found between the eleven schizophrenics, their eight non-medicated cotwins or any of the control groups (Table 1). Our subjects did not differ in mean age and, in common with previous work, there did not appear to be any effect of sex on PST activity (BONHAM CARTER er al., 1981) or any correlation between the individual PST M and P activities in the group as a whole (r= 0.10) (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). We therefore decided to combine all the twin groups to estimate the genetic contribution to enzyme activity.
PLATELETPHENOLSULPHOTRANSFERASE ACTIVITY IN TWINS TABLE
1. PLATELET PST
305
ACTIVITIESIN SCHIZOPHRENICSAND CONTROLS(NMOL PRODUCT FORMED/W PROTEIN/IO MIN INCUBATION; MEAN k SEM)
Age Group
N
(mean k SEM)
Discordant schizophrenic twins Schizophrenics MZ MZandDZ Well co-twins MZ MZandDZ
I 11 7 8
38.0 f 4.2 40.3 + 3.9 38.024.2 38.2 k 3.6
0.34 0.34 0.36 0.35
f 0.03 zk 0.03 k 0.04 f 0.04
0.07 0.07 0.08 0.08
* f k +
0.02 0.01 0.02 0.01
12 14 12 16
37.9 37.6 40.0 40.4
0.37 0.36 0.32 0.35
f 0.03 -+ 0.02 ” 0.02 -c 0.02
0.07 0.09 0.09 0.08
f + + f
0.01 0.01 0.01 0.01
Controls Females
MZ DZ MZ DZ
Males
k f It 2
PST-M
4.6 5.0 4.9 3.5
PST-P
Demonstration of a genetic effect depends on finding significantly greater similarity between members of monozygotic (MZ) twin pairs than among dizygotic (DZ) twin pairs. MZ twins always share 100% of their genes, while DZ twins share an average of 50%, though the individual members of a given DZ pair may share anything from 0 to 100% of the genes influencing a particular trait, depending on the chance assortment of genes at conception. In addition, the sensitivity and accuracy of the experimental measurement of the trait must be sufficient to demonstrate the similarity of the twin pairs compared with the range of variation in the sample as a whole. It will be seen from Table 2 that the MZ twins are significantly more alike than the DZ twins both for PST M and PST P. Table 3 shows that interpair variances, which reflect the range of variation in enzyme activity in each twin group, are quite similar for MZ and DZ twins, for each form of the enzyme. The twin intraclass correlation r, calculated by the formula ,_leIa, Ze + Ia where Ze and laare interpair and intrapair variances respectively, shows the correlation values for each twin pair against the background of total variation in the sample, and significance can be tested by comparing the F ratio of Ze/Za. Table 3 shows that MZ twins are significantly correlated for PST M, while DZ twins not. For PST P, both groups show significant correlations, though this is greater for TABLE 2. INTRAPAIR DIFFERENCES IN ENZYME ACTIVITY: MZ vs DZ Twin
Intrapair difference*
Intrapair variance
Fratio
P
0.00132 0.00390
2.96
0.025
0.00033 0.00127
3.85
0.01
PST M MZ (N= 19) DZ (N= 16)
0.042 + 0.01 0.071 f 0.01
MZ (N= 19) DZ (N= 16)
0.019 f 0.004 0.036 f 0.01
PST P
*Mean + SEM.
of its are the
A. M. REVELEY
306 TABLE Twin
group
D.F.
3.THE
GENETIC
el
al.
CONTRIBUTION
Variance
TO
PST ACTIVITY
Twin correlation ‘r’
F ratio
P
MZ
Intrapair Interpair
19 18
PST M 0.00132 0.00758
0.70
5.75
0.001
DZ
Intrapair Interpair
16 15
0.00390 0.00632
0.24
1.62
ns
MZ
lntrapair Interpair
19 18
PST P 0.00033 0.00353
0.83
10.563
0.001
DZ
Intrapair Interpair
16 15
0.00127 0.00367
0.48
2.887
0.025
MZ twins. Eliminating the seven MZ and one DZ schizophrenic pairs from the analyses did not affect the results (for PST P rMZwas 0.85 and rDZ0.24; for PST M rMZwas 0.88 and rDZ 0.44). The twin correlation can be directly interpreted as the proportion of variance roughly attributable to genetic factors, or “heritability” of the trait. Such an interpretation must be an oversimplification of the genetic and environmental influences and interrelationships that underlie the enzyme activity; for example, it takes no account of shared environment, dominance effects or gene-environment interaction. Nevertheless, we believe it to be a useful shorthand estimate. For MZ twins the correlation can be used directly, expressed as a percentage; for DZ twins it must first be doubled to account for the fact that DZ pairs can only be expected to share half their genes. Both estimates should be roughly comparable but, of course, there is no means of knowing exactly what percentage of the genetic constitution for either form of PST activity is shared by this particular group of DZ twins, so the DZ estimates are likely to be less accurate than those for the MZ twins. Thus for PST M, this rough heritability is 70% based on the MZ twins and 48% based on the DZs and for PST P, heritability is 83% based on the MZs and 96% based on the DZ pairs. DISCUSSION Both platelet PST M and PST P activities appear to be under a high degree of genetic control and the lack of correlation between the individual PST M and P activities confirms previous findings that control of these enzymes is separate (BONHAM CARTER et al., 1981, 1983; MWALUKO and WEINSHILBOUM, 1982). The genetic contribution appears slightly more marked, and is somewhat more consistent across MZ and DZ groups, for PST P activity. This finding suggests that there is greater environmental influence on PST M activity, which could either be introduced by factors operating in vivo on the twins themselves, e.g. diet, or by greater variation in the assay procedure. Even so (admittedly, the argument is somewhat circular), our finding of a significant genetic effect validates the experimental method used to monitor the trait. Our group of eleven schizophrenics is far too small to form the basis for a confident assertion that altered platelet PST activity is not implicated in the pathogenesis of
PLATELETPHENOLSULPHOTRANSFERSEACTIVITY IN TWINS
307
schizophrenia. The possibility remains that in a larger series a subgroup with altered platelet PST activity might be distinguished. Our demonstration that both forms of the enzyme are under a substantial degree of genetic control will allow future studies to proceed with greater confidence. Acknowledgements-We would like to thank themselves for their help.
Dr Ruth Sanger,
FRS for blood grouping
the twins, and the twins
REFERENCES ANDERSON, R. J. and WEINSHILBOUM, R. M. (1980) Phenolsulphotransferase in human tissue: radiochemical enzymatic assay and biochemical properties. C/in. Chim. Acta 103,79-90. BONHAM CARTER, S. M., CLOVER, V., SANDLER, M., GILLMAN, P. K. and BRIDGES, P. K. (1981) Human platelet phenolsulphotransferase: separate control of the two forms and activity range in depressive illesss. Cfin. Chim. Acfa 117,333-344. BONHAM CARTER, S. M., REIN, G., GLOVER, V., SANDLER, M. and CALDWELL, J. (1983) Human platelet phenolsulphotransferase M and P: substrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide. Er. J. clin. Pharmacol. 15,323-330. EMERY, E. H. (1976) Mefhodology in Medical Genetics, pp. 85-87. Churchill Livingstone, Edinburgh. HART, R. F., RENSKERS, K. J., NELSON, E. B. and ROTH, J. A. (1979) Localisation and characterisation of phenolsulfotransferase in human platelets. Life Sci. 24, 125-130. MWALUKO, G. and WEINSHILBOUM, R. (1982) a-Methyldopa, a-methyldopamine and a-methylnoradrenaline: substrates for the thermolabile form of human platelet phenolsulphotransferase. Br. J. c/in. Pharmacol. 14, 231-239. OSBORNE, R. H., ALDERSBERG, M. D., DE GEORGE, F. U. and WANG, C. (1959) Serum lipids, heredity and environment. A study of adult twins. Am. J. Med. 26,54-59. REIN, G., GLOVER, V. and SANDLER, M. (1981) Sulphate conjugation of biologically active monoamines and their metabolites by human platelet phenolsulphotransferase. Clin. Chim. Acfa 111,247-256. REIN, G., GLOVER, V. and SANDLER, M. (1982) Multiple forms of phenolsulphotransferase in human tissues: selective inhibition by dichloronitrophenol. Biochem. Pharmacol. 31, 1893-1897. ROTH, J. A., RIVETT, A. J. and RENSKERS, K. J. (1982) Properties of human brain phenolsulfotransferase and its role in the inactivation of catecholamine neurotransmitters. In Sulfufe Metabolism and Sulfate Conjugation (Edited by MULDER, G. I., CALDWELL, J., VAN KEMPEN, G. M. J. and VONK, R. J.), pp. 107-114. Taylor & Francis, London. SANDLER, M. and USDIN, E. (Editors) (1981) Phenolsulfotransferase in Mental Health Research. Macmillan, London. SPITZER, R. L. and ENDICOTT, J. (1977) The Schedule for Affective Disorders and Schizophrenia, Liferime Version, 3rd edn. New York State Psychiatric Institute, New York. SPITZER, R. L., ENDICOTT, J. and ROBINS, E. (1975) Research Diagnostic Criteria Instrument No. 58. New York State Psychiatric Institute, New York.