Megaloblastic Hæmopoiesis in Patients Receiving Nitrous Oxide

Amess, J. A. L.; Rees, Gareth; Burman, J. F.; Nancekievill, D. G.; Mollin, D. L.

doi:10.1016/s0140-6736(78)92941-0

Cited by 270 publications

(105 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…flowever, unlike this data in the values reported here with rat marrows are essentially the same as those found with human marrows [3]. Thus with normal rat and human marrow cells, less than 10% of [3H]thymidine is taken up after exposure to deoxyuridine.…”

Section: Discussioncontrasting

confidence: 48%

“…There was some correction of the abnormal deoxyuridine suppression test with the addition of B I~ although this was not as marked as reported by Amess et al [3] with human marrow. The correction with folate was more striking.…”

Section: Discussionmentioning

confidence: 50%

“…Administration of N 2 0 to man over several hours is followed by neutropenia and if given for 10 h [ 3 ] erythropoiesis is altered to the megaloblastic form present in vitamin B12 deficiency in man. Administration for up to five days in the treatment of tetanus [4] was accompanied by marrow failure with a megaloblastic marrow.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Inactivation of Methionine Synthase by Nitrous Oxide

et al. 1980

View full text Add to dashboard Cite

Exposure of rats to a 50% NzO/oxygen mixture led to a rapid loss of methionine synthase activity in both liver and brain. This enzyme has vitamin B12 as a cofactor. There was impaired conversion of deoxyuridine to deoxythymidine by bone marrow cells and this defect followed loss of methionine synthase activity. There was no homocystinuria. Withdrawal of N2O was followed by a relatively slow recovery of methionine synthase activity over four days. The inactivation of vitamin B12 by N2O promises to be a valuable tool in the study of vitamin B12 metabolism.The anaesthetic gas, nitrous oxide (N20), is activated in vitro in the presence of vitamin B12 and is cleaved into nitrogen and oxygen [1,2]. This is accompanied by oxidation of vitamin B12 from the cob(1)-alamin to the inative cob(I1I)alamin form.Administration of N 2 0 to man over several hours is followed by neutropenia and if given for 10 h [ 3 ] erythropoiesis is altered to the megaloblastic form present in vitamin B12 deficiency in man. Administration for up to five days in the treatment of tetanus [4] was accompanied by marrow failure with a megaloblastic marrow. Amess et al.[ 3 ] also showed that the marrow cells from patients exposed to N20 failed to incorporate deoxyuridine normally into DNA, a step requiring both vitamin B12 and folate, and this defect was partially corrected by adding vitamin B12 to the marrow suspension. In addition, intermittent inhalation of N2O as a form of addiction in man produces a neuropathy not dissimilar to that resulting from vitamin B12 deficiency and reversed by cessation of N20 inhalation [5 -71.Mice and rats exposed to N2O have impaired folate polyglutamate synthesis and abnormal deoxyuridine utilization by marrow cells despite the fact that erythropoiesis remains normoblastic [8,9]. Although methionine synthase is impaired in rats exposed to N20, methylmalonyl-CoA mutase is unaffected by the action of N2O even after propionate stimulation [lo]. Both these enzymes require BIZ as a cofactor.Experimentally it has proved very difficult to produce animals with severe B12 deficiency, and B12 neuropathy in monkeys occurs only after several years Enzyme. Methionine synthase or 5-methyltetrahydro-folate : homocysteine methyltransferase (EC 2.1.1.13).on a B12-deficient diet [ll]. For this reason it has been difficult to study the effect of B12 deficiency and its relationship to folate other than in patients with untreated pernicious anaemia. If a similar effect were produced by inactivation of B12 by N20 it would be of great value to the biochemist and an understanding of how to circumvent the toxic effects of N20 in man would make it possible to use this valuable anaesthetic and analgesic agent on a much wider scale. The purpose of this study was to investigate the effect of N2O on methionine synthase and deoxyuridine utilization in greater detail. MATERIALS AND METHODS N20Exposure. Sprague-Dawley rats were kept in specially constructed chambers in an atmosphere of 50 % N 2 0 and 50 % oxygen, humidity and C02 concentration bein...

show abstract

Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 50%

See 1 more Smart Citation

Inactivation of Methionine Synthase by Nitrous Oxide

et al. 1980

View full text Add to dashboard Cite

show abstract

“…This effect could be explained by a specific oxidative action of nitrous oxide on the cobaltmoiety of vitamin B12 (Amess et al, 1978), which causes a nearly complete inactivation of the methylcobalamin-requiring enzyme methionine synthetase or 5-methyltetrahydrofolate homocysteine methyltransferase (E.C. 2.1.1.13).…”

mentioning

confidence: 99%

Synergistic growth inhibiting effect of nitrous oxide and cycloleucine in experimental rat leukaemia

Kroes¹,

Lindemans²,

Abels³

1984

Br J Cancer

View full text Add to dashboard Cite

Summary Nitrous oxide (N20) inactivates the vitamin B12-dependent enzyme methionine synthetase with subsequent impairment of folate metabolism and a reduction of cellular proliferation. Indications exist that this effect is antagonized by S-adenosylmethionine (SAM), and it was investigated whether combination with an inhibitor of SAM synthesis, cycloleucine, would result in increased inhibition of growth in rat leukaemia model (BNML). Leukaemic growth was compared in untreated rats, in rats treated with either nitrous oxide/oxygen (1:1) or cycloleucine (50mg kg-1 i.p.), and in rats receiving both agents. Combined treatment resulted in the strongest reduction of leukaemic infiltration in spleen and liver, and this reduction often was more than the added effects of single treatments. Peripheral leukocyte counts were also lowest after combined treatment. The deoxyuridine suppression test, measuring folate-dependent de novo synthesis of thymidine, was more severely disturbed with combined treatment. Levels of vitamin B12 in plasma were reduced in rats receiving N20, but an increase in plasma folate occurred in all treated rats. These results indicate that a reduction of SAM synthesis by cycloleucine can increase the disturbance of folate metabolism that is caused by nitrous oxide, with a potentiation of the effects on leukaemic growth.

show abstract

“…2 Megaloblastic changes in the bone marrow and abnormalities of the deoxyuridine suppression test, indicating abnormal vitamin B12 or folic acid metabolism, have been noted after only 5-12 hours of nitrous oxide for postoperative analgesia. 3 The development of neuropathies has been ascribed to occul?ational exposure to nitrous oxide in dentists. '~ These haematological and neurological symptoms are similar to those of clinical vitamin B t2 deficiency.…”

mentioning

confidence: 99%

Effect of nitrous oxide anaesthesia on homocystine excretion

Bevan

Rosenblatt

Clow

et al. 1982

Can. Anaesth. Soc. J.

View full text Add to dashboard Cite

Research into the biotransformation of inhaled general anaesthetic agents, including nitrous oxide, has led to a better understanding of the underlying mechanisms. It is now known that nitrous oxide can react chemically with vitamin B~2, oxidizing Cob(I)alamin to the inactive Cob(Ill) alarnin form. Clinical and experimental evidence in mammals has confirmed that nitrous oxide toxicity, with symptoms suggestive of clinical vitamin B j2 deficiency, occurs on exposure to nitrous oxide in a way which is dose and time related and reversible on withdrawal of the nitrous oxide. Nitrous oxide depresses the two known vitamin Bt2 dependent enzymes methylmalonyl CoA mutase and methionine synthetase by inactivation of their coenzymes adenosylcobalarnin and methylcobalamin respectively. Methionine synthetase catalyses the conversion of homocystine to methionine, so interference with this reaction should cause methionine to be depleted and homocysteine to accumulate and to be excreted in the urine. We postulated that the detection of homocystinuria would therefore be an early indicator of nitrous oxide toxicity. Accordingly, we tested the first urine voided postoperatively of 41 patients undergoing nitrous oxide anaesthesia (17 neonates exposed to 50-66 per cent nitrous oxide for a mean of 3.0 hr, and 24 older patients exposed to 66 per cent nitrous oxide for a mean of 7.2 hr). None of these patients demonstrated homocystinuria.

show abstract

Megaloblastic Hæmopoiesis in Patients Receiving Nitrous Oxide

Cited by 270 publications

References 19 publications

Inactivation of Methionine Synthase by Nitrous Oxide

Inactivation of Methionine Synthase by Nitrous Oxide

Synergistic growth inhibiting effect of nitrous oxide and cycloleucine in experimental rat leukaemia

Effect of nitrous oxide anaesthesia on homocystine excretion

Contact Info

Product

Resources

About