howard@metheus.UUCP (Howard A. Landman) (03/25/84)
Here is the promised material on nitrous oxide, B-12, folate, etc. The source is: Shane & Stokstad, "The Interrelationships among Folate, Vitamin B12, and Methionine Metabolism", chapter 7 in Advances in Nutritional Research, vol. 5, Harold H. Draper (ed), Plenum Press 1983 Barry Shane is at Johns Hopkins, E.L. Robert Stokstad is at U.C. Berkeley. I have edited heavily, since this article, while excellent, is quite long and (necessarily) fairly dense going at times. For example, I omit most of the 8-page bibliography. Square braces ([]) and ellipsis (...) indicate the changes. All the below is copyright (C) 1983 Plenum Press. P.S. Some of the recent response articles have been excellent! Thanks! ----------------------------------------------------------------------------- 1. Background The interrelationship between vitamin B12 and folate metabolism in man is best illustrated by the hematologically indistinguishable, macrocytic megaloblastic anemia resulting from a deficiency of either vitamin. Large pharmacological doses of either vitamin will elicit a hematological response in patients suffering from a deficiency of either or even both vitamins. For instance, large doses of folate cause a temporary or partial hematological remission in pernicious anemia patients but fail to correct the neurological lesions that arise from prolonged vitamin B12 deprivation. ... 2. Metabolism of Folate ... 3. Methyl trap hypothesis The only known metabolic pathway common to folate, vitamin B12, and methionine is the 5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthetase) reaction. [The methyl trap hypothesis] postulates that under conditions of vitamin B12 deficiency the activity of the vitamin B12-dependent methyltransferase is significantly diminished and, as a result, a large amount of folate is trapped as the 5-methyl derivative, which cannot be reoxidized via the 5,10-methylenetetrahydrofolate reductase reaction as this reaction is essentially irreversible under physiological conditions. A functional folate deficiency ensues ... The slowdown in thymidylate and purine biosynthesis, and consequently of DNA sunthesis, results in megaloblastosis. ... 4. Effect of Methionine on Folate Metabolism ... many of the biochemical disturbances in folate metabolism in vitamin B12-deficient animals ... are exacerbated by methionine deficiency. Methionine supplementation correct many of these disturbances ... 5. Molecular Basis of Megaloblastosis Megaloblastosis is the morphological expression of deranged DNA synthesis. [Some experiments] indicate that initiation proceeds normally, but chain elongation is defective. ... 6. Effect of Nitrous Oxide Exposure of patients to nitrous oxide can lead to a megaloblastic anemia typical of that observed in vitamin B12 deficiency. The Co(I) form of vitamin B12 is susceptible to oxidation by nitrous oxide and in vitro inactivation of purified vitamin B12-dependent enzymes has been demonstrated with this agent. Because of this effect, nitrous oxide exposure of experimental animals has been used as a model for vitamin B12 deficiency effects. Rats exposed to nitrous oxide exhibit large decreases in methionine synthetase activity in liver and brain. Nitrous oxide is thought to inhibit this enzyme irreversibly by oxidizing the enzyme-B12s(Co+) complex that arises during catalysis to give a presumptively inactive enzyme-B12r(Co++) complex. In the process, nitrous oxide is reduced to nitrogen and oxygen. Hepatic methionine synthetase levels are depressed as much as 90% and return to normal 2-4 days following cessation of nitrous oxide administration. The restoration of activity presumably reflects synthesis of new enzyme. Methylcobalamin synthesis from cyanocobalamin is also depressed by nitrous oxide administration. In general, the disturbances in folate metabolism that arise as a result of nitrous oxide inhalation are consistent with those predicted by the methyl trap hypothesis [although] other interpretations have been presented ... Prolonged exposure of mice to nitrous oxide does not lead to megaloblastosis. Nitrous oxide treatment of human lymphocytes results in an abnormal deoxyuridine suppresion test, similar to that observed under conditions of cobalamin deficiency, and also inhibits the incorporation of thymidine into DNA, indicating a direct effect on DNA synthesis. ... Recent studies strongly support the concept that the neurological symptoms of vitamin B12 deficiency result from a methylation defect due to impairment of the methionine synthetase reaction. In these studies, monkeys receiving nitrous oxide developed subacute combined degeneration of the spinal cord which could be prevented by methionine administration. 7. Effect of Thyroid Function ... 8. Concluding Remarks ... References [nitrous oxide-related only] Ammes et al., "Megaloblastic haemopoisis in patients receiving nitrous oxide", Lancet 2:339, 1978 Banks et al., "Reactions of gases in solution. III. Some reactions of nitrous oxide with transition-metal complexes", J. Chem. Soc. A 1968:2886 Blackburn et al., "Reactions of cob(I)alamin with nitrous oxide and cob(III)alamin", J. Chem. Soc. Faraday Trans. 73:250, 1977 Cheng et al., "The anti-folate effect of methionine on bone marrow of normal and vitamin B12 deficient rats", Br. J. Haematol. 31:323, 1975 Deacon et al., "Studies on cobalamin and folate metabolism in rats exposed to nitrous oxide (N2O)", in Vitamin B12 (Zagalak & Friedrich, eds), p. 1055, deGruyter 1979 Deacon et al., "Impaired deoxyuridine utilization in the B12-inactivated rat and its correction by folate analogues", Biochem. Biophys. Res. Commun. 93:516, 1980 Horne & Briggs, "Effect of dietary and nitrous oxide-induced vitamin B12 deficiency on uptake of 5-methyltetrahydrofolate by isolated hepatocytes", J. Nutr. 110:223, 1980 Koblin et al., "Inactivation of methionine synthetase by nitrous oxide in mice", Anesthesiology 54:318, 1981 Lassen et al., "Treatment of Tetranus. Severa bone-marrow depression after prolonged nitrous-oxide anasthesia", Lancet 1:527, 1956 Lumb et al., "The effect of nitrous oxide inactivation of vitamin B12 on rat hepatic folate", Biochem. J. 186:933, 1980 McGing et al., "The effect of vitamin B12 inhibition in vivo: Impaired folate polyglutamate biosynthesis indicating that 5-methyltetrahydropteroylglutamte is not its usual substrate" Biochem. Biophys. Res. Commun. 82:540, 1978 McGing & Scott, "The role of methionine and vitamin B12 in folate incorporation by rat liver", Br. J. Nutr. 43:255, 1980 Perry et al., "The substrate for folate polyglutamate biosynthesis in the vitamin B12-inactivated rat", Biochem. Biophys. Res. Commun. 91:678, 1979 Quandros et al., "Interconversion of cobalamins in human lymphocytes in vitro and the influence of nitrous oxide on the synthesis of cobalamin coenzymes", in Vitamin B12 (Zagalak & Friedrich, eds), p. 1045, deGruyter 1979 Scott et al., "A study of the multiple changes induced in vivo in experimental animals by inactivating vitamin B12 using nitrous oxide", in Chemistry and Biology of Pteridines, (Kisliuk & Brown, eds) p. 335, Elsevier 1979 Scott et al., "Pathogenesis of subacute combined degeneration: a result of methyl group deficiency", Lancet 2:334, 1981 Scott & Weir, "The methyl trap hypothesis. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid-induced exacerbation of subacute combined degeneration in pernicious anemia", Lancet 2:337, 1981 -----------------------------------------------------------------------------