John R. Smythies

Cardiovascular effects of morphine and opioid peptides following intracisternal administration in chloralose-anesthetized rats.

Beta-Endorphin (0.9--2.0 nmol), morphine (11--250 nmol) and D-ala2-met-enkephalinamide (17--33 nmol) administered intracisternally produced preferential vasodepressor responses and bradycardia. Leu- (1.8--180 nmol), met-enkephalin (17--520 nmol) and alpha-endorphin (5.7--57 nmol) administered in the same way produced preferential vasopressor effects and the latter two peptides also produced bradycardia. Results obtained with naloxone (300 nmol) given intracisternally indicate that the pressor and depressor actions as well as the bradycardia are mediated through opiate receptors. The results indicate that opioid peptides may be involved in central cardiovascular control.

Disturbances of one-carbon metabolism in neuropsychiatric disorders: A review

The hypothesis that the biochemical fault in one of the schizophrenias may lie in the biochemical mechanism itself of transmethylation: the one carbon cycle, in which methionine, S-adenosylmethionine (SAM) and folic acid are involved was first put forward by Smythies (1966) following the original transmethylation hypothesis of Osmond and Smythies (1952). Recently some new data have been derived from a number of different sources that suggests a basic disorder of transmethylation mechanisms in a proportion of schizophrenics and other disorders. In a controlled study of 20 cases (Regland et al 1995a), nine showed a significant increase in blood homocysteine levels. Earlier kinetic studies (Kelsoe et al 1982; Smythies et al 1986) showing decreased activity in erythrocytes from 21 schizophrenics of the enzymes methionine-adenosyl transferase (MAT) and serine hydroxy-methyl transferase (SHMT) have been confirmed for MAT in erythrocytes in schizophrenia (Gomes-Trolin 1996). In postmortem samples from schizophrenics, there was a regionally selective decrease of Km for MAT activity in cortex gyms frontalis compared with controls (GomesTrolin, 1996). A multivariate analysis of brain tissue from

Abnormalities of one-carbon metabolism in psychiatric disorders: Study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes

Two independent lines of inquiry have implicated some disturbance of one-carbon cycle metabolism in affective disorders. Folic acid deficiency commonly leads to depression, and S-adenosylmethionine has been reported to have antidepressant properties. Methionine adenosyltransferase has been reported to be underactive in depression and schizophrenia and overactive in mania. This study reports the effects on erythrocyte methionine adenosyltransferase (MAT) kinetics (Vmax) of a 2-week treatment in a population of patients housed on a psychiatric research ward. The drug-free schizophrenic patients and depressives had, upon admission, low Vmax values, and the drug-free manic patients had high Vmax values on admission. After 2 weeks of appropriate treatment, the values for all three patient samples showed significant normalization (i.e., the levels rose in schizophrenics and depressives and fell in manics). We have further shown that pretreatment low levels of erythrocyte membrane phosphatidylcholine in depressives and high levels in manics show statistically significant normalization following 2 weeks of pharmacotherapy. The significance of these results is discussed.

ON THE MOLECULAR STRUCTURE OF RECEPTORS FOR CO-CARCINOGENS AND SOME ANTI-CANCER DRUGS

Abstract (1) A general theory of the molecular structure of receptors published previously is adapted to the problem of prostaglandin (PG) receptors. (2) On a basis of the molecular structure of PGs a tentative ‘model receptor’ in protein is specified. (3) We have discovered that other biologically active agents are also complementary to this molecular structure. (4) Possible naturally occurring PG agonists comprise the so-called violent cathartics (e.g. rhein, ricinoleic acid, emodin, chrysophanic acid, colocynthin, gambogic acid and others) and the co-carcinogens anthralin and phorbol myristate acetate. (5) Possible naturally occurring PG antagonists comprise the anti-tumor agents maytansine, acromycine, datiscoside, hellebriginin 3-acetate, hymenoflorin and mycophenolic acid. (6) Experiments to test the hypothesis are suggested.

One-carbon metabolism disturbances in affective disorders: A preliminary report

Methionine adenosyltransferase (MAT) activity (Vmax) and the relative amount of phosphatidylcholine (% PC) were measured in erythrocytes of up to 30 DSM-III diagnosed manic, 17 unipolar depressed patients, and 28 normal controls. Manic subjects had significantly higher and depressed subjects significantly lower MAT Vmax than normals. The relative amount of PC was in the low range for the depressives, and in the high range for the manics. Depressive patients present, in these tests, similar abnormalities to those seen previously in schizophrenic patients. Clinical and diagnostic implications of these findings are discussed.

Prostaglandins and cancer.

Abstract The experimental demonstration that prostaglandins (PGs) are tumor promoting agents (skin) confirms the prediction made on stereochemical grounds in this journal in 1975. This present paper explores more fully the stereochemical relations between the tumor promoting/cathartic group of drugs (such as phorbol esters, anthralin, colocynth and podophyllum), a group of anti-tumor agents (such as other phorbol esters, datiscoside, bruceantin, decumbrin and tetandrine) and two simple protein structures. (i) One is composed to two parallel strands of peptide chains some 13–14 A apart. One chain has the sequence — pSer-X-Ile-X-His-X-pSer—and the other has the same sequence in reverse. Experiments with CPK molecular models indicate that this structure could bind two PGs in co-operation with two Ca 2+ ions chelated between the phosphoserine moieties. Many drugs of the tumor promoting/cathartic class have molecular structures that enable them to bind to this model receptor in such a way as to allow Ca 2+ binding and orienting of both phosphoserines at each end correctly. Certain anti-tumor drugs have molecular structures that allow them to bind to the receptor, and to distort these key phosphoserine moieties so that they can no longer chelate a Ca 2+ ion between each phosphoserine pair. This model PG (tp) receptor (2 PG molecules) also provides a structure that is to a high degree complementary to spermine (1 molecule). (ii) The second site is an allosteric site on phospholipase A 2 adjacent to the active site as revealed by X-ray crystallography. This is complementary to lysophosphatidylethanolamine, which stimulates the enzyme and the active tumor promoting phorbol esters such as TPA. The hypothesis is therefore presented in three stages: (1) Some tumor promoters act at a PG receptor whose normal function is to chelate two Ca 2+ ions per two molecules of PG per receptor. (2) This binding may release a molecule of spermine normally bound here. (3) Other tumor promoters (e.g. TPA) act at an earlier stage, i.e. the rate controlling step in PG synthesis by phospholipase A 2 . Other data linking prostaglandins, polyamines, phospholipase A 2 and cancer are reviewed. Experiments to test these hypotheses are suggested.

The action of the alkaloids from yew (Taxus baccata) on the action potential in theXenopus medullated axon

La tassina cruda, ottenuta del tassoTaxus baccata L. ha dimostrato di ridurre linflusso Na+ del-lazione potenziale di singole preparazioni axon dal nervo sciatico della rana. La tassina cruda contiene una miscela di composti chimici e noi suggeriamo che la tassicina è il composto chimico responsabile per questo effetto.

Clinical correlations of one-carbon metabolism abnormalities

1. Ninety psychiatric inpatients with a DSM III diagnosis of schizophrenia, mania, or major depression were studied. 2. Upon admission/transfer to the Clinical Studies Unit, and prior to discharge, measurements of symptom severity (BPRS, Ham-D, Youngs Mania Scale) and blood samples were obtained. 3. Erythrocytes from these paired (admission and discharge) blood samples were assayed for methionine adenosyltransferase (MAT) activity and phosphatidylcholine (PC) content. 4. Comparisons were made between the changes in MAT Vmax, or % PC, and changes in symptom severity. 5. For the majority of the patients (79.3% of the schizophrenics; 84.6% of the depressives; and 93.8% of the manics), clinical improvement was associated with a normalization of enzyme activity. The association between changes in % PC and clinical response did not achieve significant correlation.

Role of the One-Carbon Cycle in Neuropsychiatry

This paper reviews the work available to date suggesting that elements of the one-carbon cycle may be involved in psychiatric illnesses. Two enzymes of the one-carbon cycle (in erythrocytes) – methionine adenosyltransferase (MAT) and serine hydroxymethyltransferase (SHMT) – have been reported by our group to be underactive in schizophrenia and depression and overactive in mania. This correlates with the reported anti-depressant effects of S-adenosylmethionine in humans. SHMT has also been found by another group to be underactive in serum of schizophrenics. This defect appears to be linked to abnormalities in the distribution of phospholipids in the membrane, with a relative deficiency of phosphatidylcholine and a relative excess of phosphatidylserine. Evidence showing that medications do not appear to be responsible for these findings will be presented. A review is then made of the role of transmethylation systems for lipids and proteins in cellular control systems. Lipid transmethylation is related in many systems to receptor-final messenger coupling and so to information transfer across the membrane. Protein methylation is involved in many cellular systems including chemotaxis in bacteria and leucocytes, neurotransmitter release, sperm motility and calmodulin function.

An investigation of the effects of l-methionine and related metabolites on rat behavior

l -Methionine, l -methionine plus l -serine, l -cysteine, l -serine, and betaine were tested on a modified discriminated Sidman avoidance schedule in rats. Daily injections of 250 mg/kg of these compounds were administered for at least 28 consecutive days. Schedule performance in the rat was monitored during this period and compared to preinjection saline controls. The results indicated that only methionine had significant behavior-disrupting effects. The disruption was removed by the addition of serine, suggesting that the methionine disrupting effect may have been due to one of the metabolites of methionine—homocysteine.