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Biomedical subjects

M Lumb

Publications and source records attributed to M Lumb.

At least 37 records · Page 2Linked to original sources
PubMed1983

Effect of nitrous oxide-induced inactivation of vitamin B12 on glycinamide ribonucleotide transformylase and 5-amino-4-imidazole carboxamide transformylase.

Exposure to nitrous oxide (N2O) in vivo is accompanied by oxidation of cob[I]-alamin to the inactive cob[III]alamin [1]. There is loss of methionine synthetase activity [2] and evidence of depressed supply of single carbon units at the formate level of oxidation [3,4,5]. We measured the effect of inactivation of B12 on the folate-dependent transformylases concerned in purine synthesis. After 24 h exposure to N2O there was a significant fall in glycinamide ribonucleotide transformylase (EC 2.1.2.2) and a significant increase in 5-amino-4-imidazole carboxamide transformylase (EC 2.1.2.3).

Acyltransferases↗
PubMed1983

Increased urinary excretion of formiminoglutamic acid in nitrous-oxide-treated rats and its reduction by methionine.

Inhalation of nitrous oxide oxidises cob(I)alamin and inactivates methionine synthetase of which cobalamin is a co-enzyme. The biochemical changes in the rat following exposure to nitrous oxide resemble in some detail the changes present in patients with untreated pernicious anemia due to deficiency of cobalamin. There is a marked increase in the excretion of formiminoglutamic acid in the urine following exposure to nitrous oxide. A significant decrease is produced, while on N2O, by giving methionine. The explanation for these findings is discussed in the light of recent data on the effects of cobalamin inactivation.

Animals↗
PubMed1983

Studies on the haemopoietic toxicity of nitrous oxide in man.

Nitrous oxide inactivates vitamin B12 and in man can produce a megaloblastic anaemia. Haematological and biochemical changes were studied in nine surgical patients ventilated with 70% N2O for up to 24 h and in three control patients. There was a rise in the numbers of hypersegmented neutrophils in peripheral blood following N2O. Serial bone marrow aspirates showed gross megaloblastic change after 24 h of N2O which had reverted to normoblastic but dyserythropoietic haemopoiesis by 1 week. Giant forms of early myeloid precursors were also seen after 24 h ventilation with N2O but by 1 week abnormalities were evident in more mature cells, metamyelocytes and segmented neutrophils. Megaloblastosis was associated with abnormal dU suppression which showed a correction pattern similar to that seen in vitamin B12 deficiency. Administration of N2O was also associated with a progressive rise in serum folate and fall in serum methionine levels. No similar patterns were seen in the three control patients.

Anesthesia, General↗
PubMed1983

Chronic cobalamin inactivation impairs folate polyglutamate synthesis in the rat.

Nitrous oxide, by inactivating cobalamin in vivo, produces a suitable animal model for cobalamin 'deficiency.' The synthesis of folate polyglutamate with tetrahydrofolate as substrate is severely impaired in the N2O-treated rat, but is normal with formyltetrahydrofolate as substrate. Methionine restores the capacity of the N2O-treated rat to utilize tetrahydrofolate the minimum effective dose being 16 mumol. S-Adenosylmethionine was somewhat less effective than methionine but 5'methylthioadenosine, a product of S-adenosylmethionine metabolism, was significantly more effective than methionine in correcting the defect in folate polyglutamate synthesis. 5'Methylthioadenosine is metabolised to yield formate. It is suggested that these compounds have their effect in correcting folate polyglutamate synthesis by supplying formate for the formylation of tetrahydrofolate. Formyltetrahydrofolate, at least in the cobalamin-inactivated animal, is the required substrate for folate polyglutamate synthesis. Cobalamin is concerned with the maintenance of normal levels of methionine and this in turn is a major source of formate through S-adenosylmethionine and 5'methylthioadenosine.

Adenosine↗
PubMed1982

A comparison of tetrahydrofolate and 5-formyltetrahydrofolate in correcting the impairment of thymidine synthesis in pernicious anaemia.

5-formyltetrahydrofolate and tetrahydrofolate were added to marrow cells from patients with untreated pernicious anaemia at 1, 5 and 50 nmol doses in the deoxyuridine suppression test. At all 3 dose levels formyltetrahydrofolate was significantly more effective in correcting the defect of thymidine synthesis in pernicious anaemia, than tetrahydrofolate. The data suggest that formylation of tetrahydrofolate is necessary for its normal utilization.

Anemia, Pernicious↗
PubMed1982

Urinary folate loss following inactivation of vitamin B12 by nitrous oxide in rats.

Rats were injected with [2-14C]H4PteGlu daily for 3 d and thereafter one group left in air and a second group in an atmosphere of nitrous oxide/oxygen (1/1). Nitrous oxide inactivates cobalamin. The N2O-treated rats excreted large amounts of L. casei-active folate into the urine. The urinary folate co-chromatographed with authentic 3H-labelled 5-methyltetrahydrofolate. Both groups of animals excreted 14C-labelled breakdown products in the urine but there was no evidence of increased folate catabolism in the N2O-treated rats. It was concluded that the folate deficiency that develops in the N2O-treated rat is due to massive urinary loss of folate. This appears to be secondary to impaired cellular uptake of folate which leads to a raised plasma folate level.

Animals↗
PubMed1981

Changes in tissue folates accompanying nitrous oxide-induced inactivation of vitamin B12 in the rat.

The anesthetic gas, nitrous oxide, oxidizes cob(I)alamin and thus inactivates methionine synthetase which requires cobalamin as a coenzyme. The effect on folates in liver, kidney, marrow, plasma, and brain in rats breathing a 1/1 nitrous oxide/oxygen mixture is described. There is loss of folate from tissues, most marked in liver, that affects folate polyglutamates to a greater extent than folate monoglutamates. Both methyl- and nonmethyl-analogues are affected. There is a transient rise in the levels of 5-methyltetrahydropteroylpolyglutamate in all tissues 8 h after starting nitrous oxide, which falls thereafter. In marrow and brain there is also a transient rise in methyltetrahydropteroylmonoglutamate. Plasma folate increased markedly throughout the period of exposure to nitrous oxide. It is suggested that these changes are due to the action of nitrous oxide in depressing tissue uptake of folate from plasma, in promoting loss of folate into urine and in inhibiting folate polyglutamate synthesis.

Animals↗
PubMed1981

Recovery of tissue folates after inactivation of cobalamin by nitrous oxide. The significance of dietary folate.

The anesthetic gas, nitrous oxide (N2O), oxidizes the cobalt moiety in the vitamin B12 molecule and in this way inactivates methionine synthetase which requires reduced cobalamin. In rats this is followed by a disappearance of folates from the tissues, this loss being most marked in the liver. Returning the animals to a normal atmosphere leads to restoration of most of the pre-N2O folate levels within 5 days. The plasma folate, which rises on exposure to N2O, falls within several hours. The restoration of tissue folates does not take place if the rats are placed on a low folate diet after withdrawal from an N2O environment. Thus the fall in tissue folate levels is due to loss from the body either by excretion or increased catabolism and not to redistribution of folate. Return of normal folate levels requires a dietary source of folate.

Animals↗
PubMed1981

The effect of nitrous oxide-induced inactivation of cobalamin on plasma amino acid levels in the rat.

Rats were maintained in an atmosphere of equal volumes of oxygen/nitrous oxide (1/1) for up to 7 d and plasma levels of methionine, glycine, serine, histidine, homocysteine and S-methylcysteine were measured. There was a fall in plasma methionine and a rise in plasma serine levels. There were no significant changes in glycine and histidine levels. Homocysteine and S-methylcysteine were not detected in rat plasmas. The fall in plasma methionine was due to loss of cobalamin-dependent methionine synthetase activity. The rise in plasma serine may be due to decline in its metabolism via methenyltetrahydrofolate cyclohydrolase which is concerned in oxidizing the methenyl-carbon ( =CH-), initially derived as a methylene-carbon (-CH2-)from serine, to formate (-CHO).

Amino Acids↗
PubMed1981

Changes in plasma folate levels in rats inhaling nitrous oxide.

Inhalation of nitrous oxide, which inactivates vitamin B12, is followed by a rise in the plasma folate level. The concentration of plasma folate remains elevated throughout the period of exposure to nitrous oxide. Returning the rats to the air is followed by a fall to pre-exposure plasma folate levels within 24 h.

Animals↗
PubMed1981

Role of sulphasalazine in the aetiology of folate deficiency in ulcerative colitis.

Only two (2.5%) of 80 outpatients with histologically proven ulcerative colitis had folate deficiency associated with anaemia or macrocytosis. Mean folate absorption, measured using micrograms/kg body weight of a tritium-labelled physiological folate derivative, 5-methyltetrahydroteroylglutamic acid, in six newly diagnosed patients was 76.7% (normal greater than 95%) but fell to 69.4% after three months' treatment with sulphasalazine. Mean difference in individual patients was 7.5% +/- 5.2% (SD) (p less than 0.02). Mean folate absorption in four patients with megaloblastic anaemia or macrocytosis which developed during treatment with sulphasalazine was 66.3%. This rose to 82.4% after the drug was stopped. Mean difference in individual patients was 16.6 +/- 6.6% (SD) (p less than 0.001). All patients who developed anaemia or macrocytosis with sulphasalazine had additional reasons for folate deficiency. These included coeliac disease, severe nutritional deficiencies, and haemolysis. It was concluded that sulphasalazine impairs folate absorption but this only becomes significant if other reasons for folate deficiency are also present.

Adult↗
PubMed1980

Vitamin B12 regulates folate metabolism by the supply of formate.

Nitrous oxide (N2O) inactivates the B12 coenzyme involved in methionine synthesis and interrupts formation of the folate coenzyme (folate polyglutamate). Normal synthesis of folate polyglutamate is restored in the N2O-treated rat when folate carrying a single carbon unit is supplied at the formate level of oxidation. The activity of the enzyme, formyl synthetase, which links formate to tetrahydrofolate, is increased after exposure to nitrous oxide. Formate is normally derived from the oxidation of methyl groups, methionine being an important source. It is suggested that failure of methionine synthesis leads to a paucity of formate and in turn to inadequate formylation of tetrahydrofolate. Formyltetrahydrofolate is the required substrate for the synthesis of folate polyglutamate, and impairment of this step in turn compromises general folate metabolism.

Animals↗
PubMed1980

Utilization of [2-14C]tetrahydropteroylglutamic acid and 5-[G-3H]methyltetrahydropteroylglutamic acid as substrates for folate polyglutamate synthesis in fruit bats: effect of vitamin B-12-deficiency.

[2-14C]Tetrahydropteroylglutamic acid and 5-[G-3H]methyltetrahydropteroylglutamic acid were given intraperitoneally to fruit bats. Folate polyglutamates were formed in the liver from both substrates in different amounts and at different rates. The methylfolate pool appeared to remain separate from the tetrahydrofolate pool. More polyglutamate was formed from tetrahydropteroylglutamic acid than from 5-methyltetrahydropteroylglutamic acid. There was a fall in the folate content of the liver in the vitamin B-12-deficient bat and a more rapid incorporation of folates into polyglutamates but thereafter a more rapid loss of the labelled folate from liver.

Animals↗