Folic acid metabolism in vitamin B12-deficient sheep. Effects of injected methionine on liver constituents associated with folate metabolism

1. A study was made of the effects of injected l-methionine on the activity of several enzymes of folate metabolism, and on the transport of methotrexate in liver preparations from vitamin B12-deficient ewes and their pair-fed controls receiving vitamin B12. 2. The activities of dihydrofolate reductase (EC 1.5.1.3) and 5-methyltetrahydrofolate–homocysteine transmethylase were significantly decreased in the liver of vitamin B12-deficient animals, but were unaffected by l-methionine. 3. The concentration of S-adenosyl-l-methionine in the liver of deficient animals was about one-half of that in normal animals, and was restored to normal by either vitamin B12 or l-methionine. 4. Methylenetetrahydrofolate reductase (EC 1.1.1.68) from sheep liver was inhibited by S-adenosyl-l-methionine in vitro, but not by concentrations of S-adenosyl-l-methionine found in the liver of vitamin B12-deficient animals after injection of physiological amounts of l-methionine. 5. Pteroylpolyglutamate synthetase activity was significantly increased in the liver of vitamin B12-deficient animals, and was decreased by intravenous injections of l-methionine. 6. l-Methionine injections increased the initial rate of uptake of methotrexate in liver slices from deficient animals and acted synergistically with vitamin B12 to increase the quantity taken up in 40min. The failure of folate metabolism in vitamin B12 deficiency can be satisfactorily explained if l-methionine similarly affects the membrane transport of naturally occurring folates. 7. Further details of the results have been deposited as Supplementary Publication SUP 50028 (4 pages) at the British Library (Lending Division), (formerly the National Lending Library for Science and Technology), Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies may be obtained on the terms given in Biochem. J. (1973) 131, 5.

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Circulating antibody to transcobalamin II causing retention of vitamin B12 in the blood

Blood ◽

10.1182/blood.v49.6.987.bloodjournal496987 ◽

1977 ◽

Vol 49 (6) ◽

pp. 987-1000 ◽

Cited By ~ 2

Author(s):

R Carmel ◽

B Tatsis ◽

L Baril

Keyword(s):

Vitamin B12 ◽

Binding Capacity ◽

Megaloblastic Anemia ◽

Serum Vitamin ◽

Vitamin B12 Deficiency ◽

High Serum ◽

The Status ◽

B12 Deficiency ◽

Long Acting

A patient with recurrent pulmonary abscess, weight loss, and alcoholism was found to have extremely high serum vitamin B12 and unsaturated vitamin B12-binding capacity (UBBC) levels. While transcobalamin (TC) II was also increased, most of his UBBC was due to an abnormal binding protein which carried greater than 80% of the endogenous vitamin B12 and was not found in his saliva, granulocytes, or urine. This protein was shown to be a complex of TC II and a circulating immunoglobulin (IgGkappa and IgGlambda). Each IgG molecule appeared to bind two TC II molecules. The reacting site did not interfere with the ability of TC II to bind vitamin B12, but did interfere with its ability to transfer the vitamin to cells in vitro. The site was not identical to that reacting with anti-human TC II antibody produced in rabbits. Because of this abnormal complex, 57Co-vitamin B12 injected intravenously was cleared slowly by the patient. However, no metabolic evidence for vitamin B12 deficiency was demonstrable, although the patient initially had megaloblastic anemia apparently due to folate deficiency. The course of the vitamin B12-binding abnormalities was followed over 4 yr and appeared to fluctuate with the status of the patient's illness. The IgG-TC II complex resembled one induced in some patients with pernicious anemia by intensive treatment with long-acting vitamin B12 preparations. The mechanism of induction of the antibody formation in our patient is unknown.

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Vitamin B12–Loaded Buccoadhesive Films as a Noninvasive Supplement in Vitamin B12 Deficiency: In Vitro Evaluation and In Vivo Comparative Study With Intramuscular Injection

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2017.03.040 ◽

2017 ◽

Vol 106 (7) ◽

pp. 1849-1858 ◽

Cited By ~ 6

Author(s):

Soad A. Mohamad ◽

Hatem A. Sarhan ◽

Hamdy Abdelkader ◽

Heba F. Mansour

Keyword(s):

Comparative Study ◽

Vitamin B12 ◽

Intramuscular Injection ◽

Vitamin B12 Deficiency ◽

In Vitro Evaluation ◽

B12 Deficiency

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Gel Filtration Studies of Serum B12 Binding: An Abnormal Pattern in Patients with Vitamin B12 Deficiency

Blood ◽

10.1182/blood.v34.6.774.774 ◽

1969 ◽

Vol 34 (6) ◽

pp. 774-781 ◽

Cited By ~ 5

Author(s):

CHRISTINE LAWRENCE

Keyword(s):

Molecular Weight ◽

Vitamin B12 ◽

Binding Capacity ◽

Gel Filtration ◽

Vitamin B12 Deficiency ◽

Normal Serum ◽

B12 Deficiency ◽

Abnormal Pattern ◽

Normal Controls

Abstract 57CoB12 was added to serum in vitro to study its binding by the three known serum B12-binders in patients with vitamin B12 deficiency and in normal controls. Gel filtration through columns of Sephadex G-200 was used to separate the low (beta) and high (alpha1 and beta) molecular weight B12-binding fractions. Electrophoresis on filter paper was used to separate the alpha1- and beta-globulins. The alpha1-globulin fraction in the serum of B12-deficient patients bound more of the added 57CoB12 than did this fraction in normal serum, presumably because this binder of the serum endogenous vitamin B12 is much less saturated in B12-deficiency. However, the total B12 binding capacity of the alpha1-globulin (for endogenous plus added vitamin B12) was lower in B12-deficient than in normal serum. The low molecular weight beta-binder bound more added 57CoB12 in B12-deficient than in normal serum, whereas the high molecular weight beta binder had a much lower B12-binding capacity in deficient than in normal serum. These abnormalities were independent of the cause of the vitamin B12 deficiency and disappeared after successful treatment with vitamin B12.

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The effect of nitrous oxide-induced vitamin B12 deficiency on invivo folate metabolism

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(81)91207-9 ◽

1981 ◽

Vol 98 (4) ◽

pp. 983-989 ◽

Cited By ~ 7

Author(s):

S.E. Steinberg ◽

C. Campbell ◽

R.S. Hillman

Keyword(s):

Nitrous Oxide ◽

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

Folate Metabolism ◽

B12 Deficiency

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The effect of nitrous oxide inactivation of vitamin B12 on rat hepatic folate. Implications for the methylfolate-trap hypothesis

Biochemical Journal ◽

10.1042/bj1860933 ◽

1980 ◽

Vol 186 (3) ◽

pp. 933-936 ◽

Cited By ~ 35

Author(s):

M Lumb ◽

R Deacon ◽

J Perry ◽

I Chanarin ◽

B Minty ◽

...

Keyword(s):

Nitrous Oxide ◽

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

Folate Metabolism ◽

Transient Increase ◽

Initial Value ◽

B12 Deficiency ◽

Liver Folate

Rats exposed to N20 show a decrease in liver folate to about 25% of the initial value after 10 days. There is a transient increase in the amount of 5-methylterrahydropteroylpolyglutamate in the first 24 h, but thereafter the content decreases. The level of 5-methyltetrahydropterolymonoglutamate declines without any transitory increase. The transient accumulation of 5-methyltetrahydropteroylpolyglutamate is due to failure of methionine synthetase. Thereafter the decrease in the amount of methylfolate makes it improbable that trapping of methylfolate is the explanation for failure of folate metabolism in vitamin B12 deficiency.

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The Plasma Clearance and Urinary Excretion of Parenterally Administered 58Co B12

Blood ◽

10.1182/blood.v11.1.31.31 ◽

1956 ◽

Vol 11 (1) ◽

pp. 31-43 ◽

Cited By ~ 32

Author(s):

D. L. MOLLIN ◽

W. R. PITNEY ◽

S. J. BAKER ◽

J. E. BRADLEY

Keyword(s):

Urinary Excretion ◽

Vitamin B12 ◽

Plasma Clearance ◽

Vitamin B12 Deficiency ◽

Normal Subjects ◽

Normal Serum ◽

Chronic Myelocytic Leukemia ◽

Intravenous Injections ◽

Myelocytic Leukemia ◽

B12 Deficiency

Abstract Intravenous injections of 1.5 µg. of 58Co B12 were given to subjects with normal serum B12 concentrations, to patients with vitamin B12 deficiency and to patients with chronic myelocytic leukemia. The rate of plasma clearance of radioactivity after this dose was slowest in patients with chronic myelocytic leukemia and patients with pernicious anemia in severe relapse. In patients with vitamin B12 deficiency, serum B12 concentrations were estimated microbiologically at frequent intervals after the injection. There was a good correlation between the results obtained by microbiological assay and as calculated from plasma radioactivity. Significant differences were not observed between the urinary excretion of radioactivity by normal subjects and patients with B12 deficiency.

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5-Methyltetrahydrofolate related enzymes and DNA polymerase alpha activities in bone marrow cells from patients with vitamin B12 deficient megaloblastic anemia

Blood ◽

10.1182/blood.v59.4.832.bloodjournal594832 ◽

1982 ◽

Vol 59 (4) ◽

pp. 832-837

Author(s):

Y Kano ◽

S Sakamoto ◽

K Hida ◽

K Suda ◽

F Takaku

Keyword(s):

Bone Marrow ◽

Vitamin B12 ◽

Dna Polymerase ◽

Methylenetetrahydrofolate Reductase ◽

Bone Marrow Cells ◽

Megaloblastic Anemia ◽

Vitamin B12 Deficiency ◽

Dna Polymerase Alpha ◽

B12 Deficiency ◽

Marrow Cells

The activities of 5-methyltetrahydrofolate (5-CH3THF) related enzymes and DNA polymerase alpha were determined in bone marrow cells obtained from patients with vitamin B12 deficient megaloblastic anemia and compared with those from healthy volunteers and patients with hemolytic anemia. 5-CH3THF homocysteine methyltransferase activity was significantly lower than that in the control subjects. 5,10- methylenetetrahydrofolate reductase activity was only slightly elevated to that in the control subjects. DNA polymerase alpha activity was significantly higher than that in the control. High deoxyuridine suppression test values in vitamin B12 deficient bone marrow cells were improved by tetrahydrofolate, but not by 5-CH3THF. These data indicate that, even though the reverse reaction catalyzed by 5,10- methylenetetrahydrofolate reductase may be operative in vitamin B12 deficiency, it is not sufficient to correct the disturbance in folate metabolism in vitamin B12 deficiency. Increased DNA polymerase alpha activity may be due to compensation for disarranged DNA synthesis.

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C677T Methylenetetrahydrofolate Reductase and Plasma Homocysteine Levels among Thai Vegans and Omnivores

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000148 ◽

2013 ◽

Vol 83 (2) ◽

pp. 86-91 ◽

Cited By ~ 2

Author(s):

Saowanee Kajanachumpol ◽

Kalayanee Atamasirikul ◽

Phieuvit Tantibhedhyangkul

Keyword(s):

Vitamin B12 ◽

Methylenetetrahydrofolate Reductase ◽

Vitamin B12 Deficiency ◽

Mthfr C677t ◽

Mthfr Gene ◽

Serum Folate ◽

Geometric Means ◽

C677t Mutation ◽

B12 Deficiency ◽

Mthfr Mutation

Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

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5-Methyltetrahydrofolate related enzymes and DNA polymerase alpha activities in bone marrow cells from patients with vitamin B12 deficient megaloblastic anemia

Blood ◽

10.1182/blood.v59.4.832.832 ◽

1982 ◽

Vol 59 (4) ◽

pp. 832-837 ◽

Cited By ~ 8

Author(s):

Y Kano ◽

S Sakamoto ◽

K Hida ◽

K Suda ◽

F Takaku

Keyword(s):

Bone Marrow ◽

Vitamin B12 ◽

Dna Polymerase ◽

Methylenetetrahydrofolate Reductase ◽

Bone Marrow Cells ◽

Megaloblastic Anemia ◽

Vitamin B12 Deficiency ◽

Dna Polymerase Alpha ◽

B12 Deficiency ◽

Marrow Cells

Abstract The activities of 5-methyltetrahydrofolate (5-CH3THF) related enzymes and DNA polymerase alpha were determined in bone marrow cells obtained from patients with vitamin B12 deficient megaloblastic anemia and compared with those from healthy volunteers and patients with hemolytic anemia. 5-CH3THF homocysteine methyltransferase activity was significantly lower than that in the control subjects. 5,10- methylenetetrahydrofolate reductase activity was only slightly elevated to that in the control subjects. DNA polymerase alpha activity was significantly higher than that in the control. High deoxyuridine suppression test values in vitamin B12 deficient bone marrow cells were improved by tetrahydrofolate, but not by 5-CH3THF. These data indicate that, even though the reverse reaction catalyzed by 5,10- methylenetetrahydrofolate reductase may be operative in vitamin B12 deficiency, it is not sufficient to correct the disturbance in folate metabolism in vitamin B12 deficiency. Increased DNA polymerase alpha activity may be due to compensation for disarranged DNA synthesis.

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