- Email: [email protected]
ORAL CONTRACEPTIVES, DEPRESSION, AND AMINOACID METABOLISM
1288 is justified in alive.
giving
up his endeavour to
keep
a
patient
Secondly, it is questionable to what extent any change in the definition of death would improve the supply of cadaveric organs for transplantation. It seems more likely that this could be achieved simply by better communication between doctors caring for dying patients and doctors caring for patients who need organ transplants-without any need to infringe the time-honoured methods of diagnosing death. Perhaps this kind of communication will become easier when all suspicions that transplant surgeons advocate unseemly haste in declaring the deaths of potential donors are allayed. Cardiff Royal Infirmary, Newport Road, Cardiff CF2 1SZ.
DAVID L. CROSBY.
TABLE II-EFFECT OF PYRIDOXINE AND HYDROCORTISONE ON RAT BRAIN 5-HYDROXYTRYPTAMINE
No. of determinations shown in * Different from control P<0-001.
parentheses.
t 25 mg./kg. pyridoxine injected 1800 hours day 1; 25 mg./kg. pyridoxine+5 mg./kg. hydrocortisone injected 0930 hours day 2. Sacrifice 1530 hours.
t As above except that
1
mg./kg. pyridoxine given.
that found after hydrocortisone injection. Kynurenine and 3-hydroxykynurenine, in common with some other ot aminoacids, decreased the uptake of labelled tryptophan into brain slices.7 While it is true that animal experiments may have only limited applicability to human metabolism (see the suggestionthat the rate dependent step in brain 5-H.T. synthesis may be the pyridoxal dependent decarboxylation of 5-H.T.P. in the human, but not in the rat), these findings and related observations, which have already been discussed,9 may be of relevance to biochemical changes in to
ORAL
CONTRACEPTIVES, DEPRESSION,
AND
AMINOACID METABOLISM were interested in the observations of Dr. Rose and Miss Braidman (May 23, p. 1117) on the effect of oestrogens on tryptophan oxygenase. The suggestions that high tryptophan-oxygenase activity could cause either low plasma-tryptophan or a functional deficiency of pyridoxine were discussed with reference to depression and low brain 5-hydroxytryptamine. We have been investigating in rats the hypothesis that high tryptophan-oxygenase activity might divert tryptophan metabolism away from the 5-hydroxytryptamine pathway. High tryptophan-oxygenase activity, induced by hydrocortisone, was followed by a decrease in brain 5-hydroxytryptamine (5-H.T.) and its metabolite 5-hydroxyindole acetic acid (5-H.I.A.A.), suggesting decreased 5-H.T. synthesis.l Injection of oxygenase inhibitors with the hydrocortisone prevented the rise in enzyme activity and the subsequent 5-H.T. fall.2 A transient fall of plasma-tryptophan occurred at about the time that the oxygenase activity was greatest. However, there was no significant change of brain tryptophan at this time (table I). Furthermore, pyridoxine did not prevent the fall of rat brain 5-H.T. after hydrocortisone (table II), the lower pyridoxine dose (1 mg. per kg.) being comparable to that given by Winston3 to subjects on oral contraceptives and which apparently caused remission of their drug-induced
SIR,-We
depression. A possible cause of low brain 5-H.T. in women on oral contraceptives is suggested by the report of Rose 4,6 that these subjects excrete high levels of certain tryptophan metabolites after a tryptophan load and by the report of Toseland and Price 6 that 3-hydroxyanthranilic acid excretion was high without loading. We have found that administration to rats of kynurenine, 3-hydroxykynurenine, or 3-hydroxyanthranilic acid, metabolites formed after oxygenase action, caused a fall of brain 5-H.T.’ comparable 1. 2. 3. 4. 5. 6. 7.
Curzon, G., Green, A. R. Life Sci. 1968, 7, 657. Green, A. R., Curzon, G. Nature, Lond. 1968, 220, 1095. Winston, F. Lancet, 1969, i, 1209. Rose, D. P. Nature, Lond. 1966, 210, 196. Rose, D. P. Clin. Sci. 1966, 31, 265. Toseland, P. A., Price, S. Br. med. J. 1969, i, 777. Green, A. R., Curzon, G. Biochem. Pharmac. (in the press).
depression. Department of Chemical Pathology, Institute of
Neurology, Queen Square,
London W.C.1.
WORK OF THE ANÆSTHETIST SIR,-Dr. Rubin (May 30, p. 1170) argues the orthodox point of view admirably, but does the argument stand up to scrutiny ? How, for example, can it be said that " induction, maintenance, and recovery from anaesthesia should never be considered routine ", when that is precisely what " they have become ? Or that a small error or misjudgment of any anxsthetic may have serious and irreversible consequences for the patient ", when we anaesthetists know that even the most decrepit patient will come to harm only if we make a monumental blunder ? Dr. Rubin states that, because of the danger from small " errors or misjudgments, the young healthy patient undergoing minor surgery deserves as skilled anaesthetic care as the sick patient having a major procedure ", and presumably, therefore, requires the services of a consultant anaesthetist. How can this be reconciled with the fact that each year in England and Wales more than a million dental outpatients are anaesthetised by dentists, with a mortality as low, perhaps lower, than when this work is done by consultant anaesthetists ? In the vast mass of our operating-theatre work, practically the only skill required is for intubation; once the tube is in, we have merely to watch progress. Dr. Rubin agrees that " nurse anaesthetists can readily acquire the technical 8.
Robins, E., Robins, J. M., Croninger, A. B., Moses, S. G., Spencer, S., Hudgens, R. W. Biochem. Med. 1967, 1, 240. 9. Curzon, G. Br. J. Psychiat. 1969, 115, 1367.
TABLE I-EFFECT OF HYDROCORTISONE ON TRYPTOPHAN METABOLISM IN THE RAT
No. of determinations shown in
A. R. GREEN M. H. JOSEPH G. CURZON.
parentheses.
*
Different from control p<0 01.
giving
up his endeavour to
keep
a
patient
Secondly, it is questionable to what extent any change in the definition of death would improve the supply of cadaveric organs for transplantation. It seems more likely that this could be achieved simply by better communication between doctors caring for dying patients and doctors caring for patients who need organ transplants-without any need to infringe the time-honoured methods of diagnosing death. Perhaps this kind of communication will become easier when all suspicions that transplant surgeons advocate unseemly haste in declaring the deaths of potential donors are allayed. Cardiff Royal Infirmary, Newport Road, Cardiff CF2 1SZ.
DAVID L. CROSBY.
TABLE II-EFFECT OF PYRIDOXINE AND HYDROCORTISONE ON RAT BRAIN 5-HYDROXYTRYPTAMINE
No. of determinations shown in * Different from control P<0-001.
parentheses.
t 25 mg./kg. pyridoxine injected 1800 hours day 1; 25 mg./kg. pyridoxine+5 mg./kg. hydrocortisone injected 0930 hours day 2. Sacrifice 1530 hours.
t As above except that
1
mg./kg. pyridoxine given.
that found after hydrocortisone injection. Kynurenine and 3-hydroxykynurenine, in common with some other ot aminoacids, decreased the uptake of labelled tryptophan into brain slices.7 While it is true that animal experiments may have only limited applicability to human metabolism (see the suggestionthat the rate dependent step in brain 5-H.T. synthesis may be the pyridoxal dependent decarboxylation of 5-H.T.P. in the human, but not in the rat), these findings and related observations, which have already been discussed,9 may be of relevance to biochemical changes in to
ORAL
CONTRACEPTIVES, DEPRESSION,
AND
AMINOACID METABOLISM were interested in the observations of Dr. Rose and Miss Braidman (May 23, p. 1117) on the effect of oestrogens on tryptophan oxygenase. The suggestions that high tryptophan-oxygenase activity could cause either low plasma-tryptophan or a functional deficiency of pyridoxine were discussed with reference to depression and low brain 5-hydroxytryptamine. We have been investigating in rats the hypothesis that high tryptophan-oxygenase activity might divert tryptophan metabolism away from the 5-hydroxytryptamine pathway. High tryptophan-oxygenase activity, induced by hydrocortisone, was followed by a decrease in brain 5-hydroxytryptamine (5-H.T.) and its metabolite 5-hydroxyindole acetic acid (5-H.I.A.A.), suggesting decreased 5-H.T. synthesis.l Injection of oxygenase inhibitors with the hydrocortisone prevented the rise in enzyme activity and the subsequent 5-H.T. fall.2 A transient fall of plasma-tryptophan occurred at about the time that the oxygenase activity was greatest. However, there was no significant change of brain tryptophan at this time (table I). Furthermore, pyridoxine did not prevent the fall of rat brain 5-H.T. after hydrocortisone (table II), the lower pyridoxine dose (1 mg. per kg.) being comparable to that given by Winston3 to subjects on oral contraceptives and which apparently caused remission of their drug-induced
SIR,-We
depression. A possible cause of low brain 5-H.T. in women on oral contraceptives is suggested by the report of Rose 4,6 that these subjects excrete high levels of certain tryptophan metabolites after a tryptophan load and by the report of Toseland and Price 6 that 3-hydroxyanthranilic acid excretion was high without loading. We have found that administration to rats of kynurenine, 3-hydroxykynurenine, or 3-hydroxyanthranilic acid, metabolites formed after oxygenase action, caused a fall of brain 5-H.T.’ comparable 1. 2. 3. 4. 5. 6. 7.
Curzon, G., Green, A. R. Life Sci. 1968, 7, 657. Green, A. R., Curzon, G. Nature, Lond. 1968, 220, 1095. Winston, F. Lancet, 1969, i, 1209. Rose, D. P. Nature, Lond. 1966, 210, 196. Rose, D. P. Clin. Sci. 1966, 31, 265. Toseland, P. A., Price, S. Br. med. J. 1969, i, 777. Green, A. R., Curzon, G. Biochem. Pharmac. (in the press).
depression. Department of Chemical Pathology, Institute of
Neurology, Queen Square,
London W.C.1.
WORK OF THE ANÆSTHETIST SIR,-Dr. Rubin (May 30, p. 1170) argues the orthodox point of view admirably, but does the argument stand up to scrutiny ? How, for example, can it be said that " induction, maintenance, and recovery from anaesthesia should never be considered routine ", when that is precisely what " they have become ? Or that a small error or misjudgment of any anxsthetic may have serious and irreversible consequences for the patient ", when we anaesthetists know that even the most decrepit patient will come to harm only if we make a monumental blunder ? Dr. Rubin states that, because of the danger from small " errors or misjudgments, the young healthy patient undergoing minor surgery deserves as skilled anaesthetic care as the sick patient having a major procedure ", and presumably, therefore, requires the services of a consultant anaesthetist. How can this be reconciled with the fact that each year in England and Wales more than a million dental outpatients are anaesthetised by dentists, with a mortality as low, perhaps lower, than when this work is done by consultant anaesthetists ? In the vast mass of our operating-theatre work, practically the only skill required is for intubation; once the tube is in, we have merely to watch progress. Dr. Rubin agrees that " nurse anaesthetists can readily acquire the technical 8.
Robins, E., Robins, J. M., Croninger, A. B., Moses, S. G., Spencer, S., Hudgens, R. W. Biochem. Med. 1967, 1, 240. 9. Curzon, G. Br. J. Psychiat. 1969, 115, 1367.
TABLE I-EFFECT OF HYDROCORTISONE ON TRYPTOPHAN METABOLISM IN THE RAT
No. of determinations shown in
A. R. GREEN M. H. JOSEPH G. CURZON.
parentheses.
*
Different from control p<0 01.