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69. Pharmacological effects of methionine sulphoximine
BLEACHING AND MATURING AGENTS zation and its effect on blood-clotting factors in an inbred strain of mice. Nature, Land. 193, 387. 67. TOXICITY CAUSED BY ETHYLENE OXIDE STERILIZATION An earlier report (Allen et al. Nature, Land. 1962, 193, 387) described the occurence of a haemorrhagic condition following the ingestion by rats of pine shavings that had been sterilized with ethylene oxide. The condition which was due to a blood clotting factor deficiency, could be reproduced by feeding to rats either extracts of such shavings or commercial ethylene glycol. The present report states that neither oral nor intravenous administration of liquid ethylene oxide produced the haemorrhagic state in these animals. Allen, R. C., Meier, H. & Hoag, W. G. (1962). The toxic effects on blood clotting factors of ethylene glucol produced by ethylene oxide sterilization. Fed. Proe. 21,452.
Bleaching and Maturing Agents 68. PSYCHOSIS INDUCED BY METHIONINE SULPHOXIMINE In rats, methionine sulphoximine (I) has been shown to enhance the activity of 2 amino acid analogues used as anti-tumour agents. For this reason 1 was given to 7 patients with inoperable cancer. An oral dose of 200-400 mg daily produced frank hallucinations, disorientation and marked agitation in 5 patients. These subsided 1-3 days after its withdrawal in 4 patients. In a single patient who was also receiving DON (6-diazo-oxo-L-norleucine), the mental and neurological abnormalities produced persisted after withdrawal. In one patient, the onset of psychosis was prevented by simultaneous ingestion of a large excess of methionine. [This report is of interest in showing that I, the toxic agent of agene poisoning in animals, is capable of producing severe mental disturbances in man also.] Krakoff, I. H. (1961). Effect of methionine sulphoximine in man. Clin. Pharmacol. Ther. 2, 599. 69. P H A R M A C O L O G I C A L EFFECTS OF METHIONINE SULPHOXIMINE Methionine sulphoximine (1), the toxic agent of agene poisoning, has already been shown to inhibit the incorporation of methionine (II) into brain protein (Folbergova, Nature, Land. 1962, 194, 871). In the present study, administration of I to rats was shown to enhance the incorporation of II labelled with 3sS into the proteins of the spleen but not of the liver. Increase of liver total lipids and fatty acid esters indicated that I gave rise to liver damage; exactly the opposite however occurred in the spleen. Changes in the blood picture were also observed; decreases in the lymphocyte, neutrophil and reticulocyte counts were noted. Excretion of mucopoly-
119
saccharides in the urine was also observed; in this respect the effects of I upon rats resembled those of irradiation. [This paper was seen in abstFact form only, as no translation of the original Czech was available.] Kolou~ek, J., Dienstbier, Z. & Michalec, (~. (1961). VLIV Methionin-sulfoximinu na metabolismus jater a sleziny u krys. Acta Univ. Carolinae 14, 95. 70. EFFECT OF DL-METHIONINE SULPHOXIMINE UPON BRAIN SLICES It has been established that methionine sulphoximine (1) produces tile convulsions seen in agene poisoning, hi vivo. I produces several metabolic disturbances in the brain, one of which is the inhibition of the incorporation of methionine (ll) into brain proteins (Gershoff, Amer. J. Physiol. 1956, 184, 43). In order to elucidate further the action of 1 in respect of brain protein metabolism, a study has now been made of the effect of I upon the incorporation of II into brain proteins under in vitro conditions in slices of brain cortex. No reduction of the rate of this process was found under the conditions of the experiment in rat, guinea-pig or rabbit brain slices, and preliminary experiments also indicated a similar result with homogenates of brain cortex. It was unlikely that permeability phenomena could have led to these results. Other possible factors which might be considered, in relation to the known action of I in reducing the incorporation of II into brain proteins were: (a) the possible activity of metabolites of I produced in tissues other than brain or (b) that alteration of brain intracellular brain glutamine levels was involved. Folbergrova, J. (1962). Effect of DL-methionine sulphoximine on incorporation of ssS-methionine into proteins of brain cortex slices. Nature, Lond. 194, 871. 71. CHRONIC FEEDING TESTS OF VARIOUS IMPROVED FLOURS Bread crumbs from flour treated with agene at 600 ppm caused the appearance of hysteria after 3 days in dogs. Crumbs made from flour, improved with 300 ppm ascorbic acid or by prolonged aeration, did not produce harmful effects over periods ranging from 12-20 months. Impey, S. G., Moore, T. & Sharman, I. M. (1961). Effect of flour treatment on the suitability of bread as food for dogs. J. Sci. Fd Agric. 12, 729.
Processing Aids 72. EFFECT OF EDTA ON IRON AND CALCIUM UTILIZATION Earlier experiments (Hawkins et al. Canad. J. Biachem. 1962, 38, 813) had shown that the addition of 1% disodium EDTA to a diet that contained more than optimal amounts of iron and calcium, lowered
Bleaching and Maturing Agents 68. PSYCHOSIS INDUCED BY METHIONINE SULPHOXIMINE In rats, methionine sulphoximine (I) has been shown to enhance the activity of 2 amino acid analogues used as anti-tumour agents. For this reason 1 was given to 7 patients with inoperable cancer. An oral dose of 200-400 mg daily produced frank hallucinations, disorientation and marked agitation in 5 patients. These subsided 1-3 days after its withdrawal in 4 patients. In a single patient who was also receiving DON (6-diazo-oxo-L-norleucine), the mental and neurological abnormalities produced persisted after withdrawal. In one patient, the onset of psychosis was prevented by simultaneous ingestion of a large excess of methionine. [This report is of interest in showing that I, the toxic agent of agene poisoning in animals, is capable of producing severe mental disturbances in man also.] Krakoff, I. H. (1961). Effect of methionine sulphoximine in man. Clin. Pharmacol. Ther. 2, 599. 69. P H A R M A C O L O G I C A L EFFECTS OF METHIONINE SULPHOXIMINE Methionine sulphoximine (1), the toxic agent of agene poisoning, has already been shown to inhibit the incorporation of methionine (II) into brain protein (Folbergova, Nature, Land. 1962, 194, 871). In the present study, administration of I to rats was shown to enhance the incorporation of II labelled with 3sS into the proteins of the spleen but not of the liver. Increase of liver total lipids and fatty acid esters indicated that I gave rise to liver damage; exactly the opposite however occurred in the spleen. Changes in the blood picture were also observed; decreases in the lymphocyte, neutrophil and reticulocyte counts were noted. Excretion of mucopoly-
119
saccharides in the urine was also observed; in this respect the effects of I upon rats resembled those of irradiation. [This paper was seen in abstFact form only, as no translation of the original Czech was available.] Kolou~ek, J., Dienstbier, Z. & Michalec, (~. (1961). VLIV Methionin-sulfoximinu na metabolismus jater a sleziny u krys. Acta Univ. Carolinae 14, 95. 70. EFFECT OF DL-METHIONINE SULPHOXIMINE UPON BRAIN SLICES It has been established that methionine sulphoximine (1) produces tile convulsions seen in agene poisoning, hi vivo. I produces several metabolic disturbances in the brain, one of which is the inhibition of the incorporation of methionine (ll) into brain proteins (Gershoff, Amer. J. Physiol. 1956, 184, 43). In order to elucidate further the action of 1 in respect of brain protein metabolism, a study has now been made of the effect of I upon the incorporation of II into brain proteins under in vitro conditions in slices of brain cortex. No reduction of the rate of this process was found under the conditions of the experiment in rat, guinea-pig or rabbit brain slices, and preliminary experiments also indicated a similar result with homogenates of brain cortex. It was unlikely that permeability phenomena could have led to these results. Other possible factors which might be considered, in relation to the known action of I in reducing the incorporation of II into brain proteins were: (a) the possible activity of metabolites of I produced in tissues other than brain or (b) that alteration of brain intracellular brain glutamine levels was involved. Folbergrova, J. (1962). Effect of DL-methionine sulphoximine on incorporation of ssS-methionine into proteins of brain cortex slices. Nature, Lond. 194, 871. 71. CHRONIC FEEDING TESTS OF VARIOUS IMPROVED FLOURS Bread crumbs from flour treated with agene at 600 ppm caused the appearance of hysteria after 3 days in dogs. Crumbs made from flour, improved with 300 ppm ascorbic acid or by prolonged aeration, did not produce harmful effects over periods ranging from 12-20 months. Impey, S. G., Moore, T. & Sharman, I. M. (1961). Effect of flour treatment on the suitability of bread as food for dogs. J. Sci. Fd Agric. 12, 729.
Processing Aids 72. EFFECT OF EDTA ON IRON AND CALCIUM UTILIZATION Earlier experiments (Hawkins et al. Canad. J. Biachem. 1962, 38, 813) had shown that the addition of 1% disodium EDTA to a diet that contained more than optimal amounts of iron and calcium, lowered