Nitrous oxide methionine synthetase

There appear also to be toxic effects. In animals, nitrous oxide has been shown to inactivate methionine synthetase which prevents the conversion of deoxyuridine to thymidine and thus has the potential for inducing megaloblastic anemia, leukopenia, and teratogenicity (44—46). A variety of epidemiologic surveys suggest positive correlations between exposure to nitrous oxide and spontaneous abortion in dental assistants (47). 

Nitrous oxide exerts a variety of its adverse effects by oxidizing vitamin Bn and rendering it inactive as a coenzyme in many essential metabolic processes. One vitamin dependent enzyme in particular, methionine synthetase, is involved in cell division and is necessary for DNA production. Adverse reproductive and hematologic effects caused by nitrous oxide are thought to be due to inactivation or dysfunction of methionine synthetase resulting in impairment of cell division. 

Impairment of methionine synthetase activity, for example, in vitamin B12 deficiency or after prolonged exposure to nitrous oxide (Section 10.9.7), will result in the accumulation of methyl-tetrahydrofolate. This can neither be utilized for any other one-carbon transfer reactions nor demethylated to provide free tetrahydrofolate. 

Methionine synthetase also catalyzes the reduction of nitrous oxide to nitrogen and in so doing generates a hydroxyl radical that results in irreversible inactivation of the enzyme (Frasca et al., 1986). Inactivation of methionine synthetase by nitrous oxide has been used as an acute model of vitamin B12... 

Horne DW, Patterson D, and Cook RJ (1989) Effect of nitrous oxide inactivation of vitamin B12-dependent methionine synthetase on the subcellular distribution of folate coenzymes In rat liver. Archives of Biochemistry and Biophysics 270, 729-33. 

One of the biochemical adverse effects of nitric oxide is inactivation of vitamin B12, with subsequent potentiation of folate deficiency (19). This effect is mediated by irreversible oxidation of the cobalt residue in vitamin B12 to its Co++ and Co forms. This leads to a reduction in methionine synthetase activity, with downstream effects on DNA synthesis. Previous studies have identified five patients with unsuspected vitamin B12 deficiency who developed subacute combined degeneration of the spinal cord following inhalation anesthesia with nitrous oxide... 

Nitrous oxide inactivates the enzyme methionine synthetase, and caution is urged in giving nitrous oxide to patients who may be deficient in vitamin B12. Low serum vitamin B12 concentrations have previously been reported in patients with sickle cell disease, but the reason for this is uncertain. Three cases of peripheral neuropathy have been reported in patients with sickle cell disease who received nitrous oxide (12-14). AU three had a history of frequent painful sickle crises, for which they received nitrous oxide for prolonged periods. Serum vitamin B12 concentrations were slightly reduced in two patients and very low in the third. The patients aU presented with difficulty in walking and paresthesia. Peripheral sensorimotor neuropathy was confirmed by nerve conduction studies. The patients all responded well to vitamin B12 injections and avoiding further exposure to nitrous oxide. Caution is therefore recommended when using nitrous oxide in patients with sickle cell disease or who are suspected of vitamin B12 deficiency. Two cases of polyneuropathy have also been reported after the use of nitrous oxide for 80 minutes and 3 hours in patients who were subsequently found to have pernicious anemia. They both responded well to hydroxocobalamin. 

While no firm underlying mechanisms have been demonstrated, some authors have suggested that irreversible oxidation of the cobalt atom in vitamin B12 by nitrous oxide can lead to inactivation of enzymes dependent on this vitamin, with resultant metabolic aberrations. Such examples have included methionine synthetase and thymidylate synthetase, which are essential in the synthetic pathways leading to the production of myelin and thymidine, respectively. Should these enzymes be impaired during the sensitive periods of in utero development, the potential for malformations may unfortunately be realized. To date, no studies have been able to demonstrate conclusively that low-level exposure to nitrous oxide is associated with a meaningful disruption of crucial metabolic functions to produce the above-described toxicity however, measures including improved waste gas-scavenging systems should be taken to minimize exposure of personnel. 

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