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PubMed1988

Correlation between serum enzymes and serum unsaturated vitamin B12 binding proteins in primary liver carcinoma.

The serum unsaturated vitamin B12-binding capacity (UBBC), unsaturated transcobalamin (UTC) I, UTC II, UTC III levels, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activities and bilirubin concentration were estimated in 61 patients with liver diseases (31 with hepatoma, 30 with viral hepatitis). The levels of serum cobalamin, UTC I, UTC III, UBBC, alanine and aspartate aminotransferases, and bilirubin were raised in both hepatoma and viral hepatitis patients. Serum UTC II was reduced in both conditions. Alkaline phosphatase activity was significantly increased in hepatoma. Four significant correlations were observed among these parameters in the hepatoma patients while only one significant correlation was observed in viral hepatitis.

Adult↗
PubMed2005

Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population.

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) is an established determinant of homocysteine plasma level (t-Hcys) while its association with coronary artery disease (CAD) seems to be more limited. In contrast, the association of the substitutions A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR) and C776G of transcobalamin (TCN) to both t-Hcys and CAD needs to be evaluated further. The objective was to evaluate the association of these polymorphisms with t-Hcys and CAD in a French population. We investigated the individual and combined effects of these polymorphisms and of vitamin B12 and folates with t-Hcys in 530 CAD patients and 248 matched healthy controls. t-Hcys was higher in the CAD group than in controls (11.8 vs 10.4 microM, P < 0.0001) and in carriers of MTRRAA and MTHFR 677TT than in those carrying the most frequent allele of both polymorphisms (13.8 vs 11.4 microM, P = 0.0102 and 12.5 vs 11.0 mM, P = 0.0065 respectively). The frequency of MTRR A allele was higher in CAD patients than in controls (0.48 [95% CI: 0.44-0.52] vs 0.38 [95% CI: 0.32-0.44], P = 0.0081) while no difference was observed for MTHFR 677T frequency. In multivariate analysis, t-Hcys > median and MTRRAA genotype were two significant independent predictors of CAD with respective odds ratios of 3.1 (95 % CI: 1.8-5.1, P < 0.0001) and 4.5 (95% CI: 1.5-13.1, P = 0.0051). In conclusion, in contrast to North Europe studies, MTRRAA genotype is a genetic determinant of moderate hyperhomocysteinemia associated with CAD in a French population without vitamin fortification.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2005

Nonradioactive vitamin B12 absorption test evaluated in controls and in patients with inherited malabsorption of vitamin B12.

BACKGROUND: Current tests for evaluation of vitamin B(12) absorption are problematic because they involve the use of radioactively labeled vitamin B(12). We describe a vitamin B(12) absorption test that circumvents this problem. METHODS: We measured cobalamin or transcobalamin saturated with cobalamin (holo-TC) 24 h after three 9-microg doses of vitamin B(12) given orally at 6-h intervals. We studied 17 patients with inherited malabsorption of vitamin B(12) attributable to Imerslund-Grasbeck syndrome (n = 13) or intrinsic factor deficiency (n = 4), their obligate heterozygous biological parents (n = 19), and healthy controls (n = 44). RESULTS: In the patients, the median (range) change of holo-TC after the B(12) load was not significant [1 (-42 to 5) pmol/L], nor was the change of cobalamin [-3 (-32 to 22) pmol/L], consistent with a lack of measurable active or passive absorption. In controls, however, the median (range) increases of holo-TC and cobalamin were 26 (-6 to 63) pmol/L and 41 (-37 to 109) pmol/L, respectively. Similarly, the parents showed increases of 23 (-2 to 47) pmol/L and 27 (-15 to 94) pmol/L. The mean areas under the ROC curves (95% confidence intervals) were 0.97 (0.93-1.0) for holo-TC and 0.87 (0.79-0.94) for cobalamin, distinguishing patients from controls. At a cutoff of 6 pmol/L for holo-TC, the diagnostic sensitivity (95% confidence interval) was 100 (81-100)%, and the diagnostic specificity was 92 (82-97)%. CONCLUSION: Measurement of holo-TC after administration of vitamin B(12) is a promising approach for evaluating vitamin B(12) absorption.

Absorption↗
PubMed2005

Measurement of total vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12 deficiency.

BACKGROUND: The standard screening test for vitamin B12 deficiency, measurement of total plasma vitamin B12, has limitations of sensitivity and specificity. Plasma vitamin B12 bound to transcobalamin (holoTC) is the fraction of total vitamin B12 available for tissue uptake and therefore has been proposed as a potentially useful alternative indicator of vitamin B12 status. METHODS: We compared the diagnostic accuracy of total vitamin B12, holoTC, and a combination of both measures to screen for metabolic vitamin B12 deficiency in an elderly cohort (age > or = 60 years). Plasma methylmalonic acid and homocysteine were used as indicators of vitamin B12 deficiency. RESULTS: Low total vitamin B12 (< 148 pmol/L) and low holoTC (< 35 pmol/L) were observed in 6.5% and 8.0%, and increased methylmalonic acid (> 350 nmol/L) and homocysteine (> 13 micromol/L) were observed in 12.1% and 17.0% of the study participants. In multiple regression models, holoTC explained 5%-6% more of the observed variance in methylmalonic acid and homocysteine than did total vitamin B12 (P < or = 0.004). ROC curve analysis indicated that total vitamin B12 and holoTC were essentially equivalent in their ability to discriminate persons with and without vitamin B12 deficiency. Individuals with low concentrations of both total vitamin B12 and holoTC had significantly higher concentrations of methylmalonic acid and homocysteine than did individuals with total vitamin B12 and/or holoTC within the reference intervals (P < 0.001). CONCLUSIONS: HoloTC and total vitamin B12 have equal diagnostic accuracy in screening for metabolic vitamin B12 deficiency. Measurement of both holoTC and total vitamin B12 provides a better screen for vitamin B12 deficiency than either assay alone.

Aged↗
PubMed2003

The role of genetic factors in the development of hyperhomocysteinemia.

Moderate hyperhomocysteinemia has been identified as a new independent risk factor for cardiovascular and neurodegenerative diseases. This fact has produced interest in the study of genetic variants involved in homocysteine metabolism and its relationship to pathogenesis. Recently, more than 15 different genes were studied for their relationship to plasma homocysteine levels. We determined the influence of genetic variants in five genes (5,10-methylenetetrahydrofolate reductase (MTHFR) 677C --> T, serine hydroxymethyltransferase (SHMT) 1420C --> T, thymidylate synthase (TS) 2R --> 3R, catechol-O-methyltransferase (COMT) 1947G --> A and transcobalamin (TC) 776C --> G) on plasma homocysteine, folic acid and parameters of vitamin B12 metabolism in 111 vegetarians (mean age: 46 +/- 15 years) and 118 healthy seniors (mean age: 82 +/- 6.5 years). Median homocysteine concentration in plasma was significantly influenced by the MTHFR genotypes in both populations. In the vegetarians the median homocysteine level was increased by 8 micromol/l in individuals homozygous for the mutation as compared to wild-type or heterozygous genotypes (20.4 micromol/l vs. 12.9 and 12.7 micromol/l, respectively). This unexpected increase was observed although the folate levels were in medium to elevated ranges. Our results suggest that vegetarians have a higher demand for folate to neutralize the genotype effect. Preclinical vitamin B12 deficiency in vegetarians may be the cause for disturbed remethylation and folate trap. Plasma homocysteine was not significantly influenced by the SHMT, TS, COMT and TC mutations. In addition, for the TC mutation a trend toward cellular vitamin B12 deficiency was observed. The methylmalonic acid (MMA) levels were slightly elevated and the holotranscobalamin-II (holoTC-II) levels decreased. In the vegetarian group a significant relationship between the COMT genotype and holoTC-II concentration in plasma was determined, whereas the high activity COMT genotype (G/G) resulted in increased levels (35 micromol/l vs. 21 micromol/l for heterozygous and low activity genotypes). The MMA levels were inversely correlated to holoTC-II concentrations. In conclusion, the study on vegetarians and seniors documents interesting lifestyle-genotype interactions. Although the TC and COMT mutations influence cellular vitamin B12 metabolism, this effect did not result in overt homocysteine elevation.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2003

Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

Clinical utility of serum holotranscobalamin as a marker of cobalamin status in elderly patients with neuropsychiatric symptoms.

Early diagnosis of cobalamin deficiency is crucial, owing to the latent nature of this disorder and the resulting possible irreversible neurological damage. A normal serum cobalamin concentration does not reliably rule out a functional cobalamin deficiency and there does not at present seem to be any single diagnostic approach to achieve this diagnosis. A new marker for cobalamin status is the serum concentration of cobalamin bound to transcobalamin II (holoTC). Because methods suitable for routine use have been unavailable until recently, the clinical value of low holoTC is still uncertain. Furthermore, there is at the moment no gold standard or true reference method to diagnose subtle cobalamin deficiency, which makes evaluation of the clinical usefulness of holoTC and the estimation of sensitivity and specificity problematic. In this study, we aimed to assess whether low holoTC concentrations are congruent with other biochemical signs of cobalamin deficiency in a group of psychogeriatric patients. The findings in the present study show that holoTC is strongly related to serum cobalamin (0.68; p<0.001 in both patients and controls). Distribution of the different markers for cobalamin/folate status in the 33 patients with low levels of serum holoTC (below 40 pmol/l) showed that 17 patients had normal levels of the other markers for cobalamin status. This may indicate poor specificity of low holoTC for cobalamin deficiency. In 23 out of 176 patients with normal levels of holoTC we observed pathological levels of other markers for cobalamin deficiency. The use of holoTC in the present study group did not give significant additional information other than that given by serum cobalamin and therefore cannot be recommended in this clinical setting.

Age Factors↗
PubMed1985

Vitamin B12 binding proteins in amniotic fluid.

The cobalamin-binding proteins in amniotic fluid are determined by assaying the unsaturated cobalamin-binding capacity of haptocorrin (R-proteins, cobalophilin, or transcobalamin I-like protein and any coexisting intrinsic factor) and non-haptocorrin. Forty-five specimens obtained by amniocentesis, and ninety-two obtained at parturition are analysed. The haptocorrin cobalamin-binding capacity increases rapidly after a gestational age of about 15 weeks. At parturition the concentration varies from 1.4 to 26.8 nmol/l. The non-haptocorrin cobalamin-binding capacity is less than 1% of the total binding capacity. The unsaturated cobalamin-binding capacities do not correlate significantly with birth weight, placental weight, or total protein concentration of the amniotic fluid. The ratio between haptocorrin concentration in amniotic fluid and maternal plasma is about 3:1. The unsaturated cobalamin-binding capacity of haptocorrin in amniotic fluid is significantly higher in pregnancies with female than with male fetuses, and is relatively high in one case of twins. It is suggested that haptocorrin in amniotic fluid originates mainly from the fetus, and may have a bacteriostatic effect.

Amniocentesis↗
PubMed1992

Cobalamin binding proteins in human seminal plasma.

Transcobalamin (TC) and haptocorrin (HC) are present in normal seminal plasma in substance concentrations ten- to twenty-fold that in blood. The results are given in range and (median). The substance concentration of seminal plasma TC is 3.6-21.9 (8.4) nmol l-1 and of seminal plasma HC 1.4-8.6 (3.0) nmol l-1. Compared to normals the substance concentration of TC is significantly lowered in post-vasectomy seminal plasma 2.2-2.9 (5.3) nmol l-1. The Stokes radius and the isoelectric points of seminal plasma TC are identical to TC in blood.

Chemical Phenomena↗
PubMed1988

Unsaturated B12-binding proteins in amniotic fluid of cystic fibrosis-affected foetus.

The authors hypothesized the possibility of quantitative or qualitative abnormalities of amniotic fluid B12-binding proteins in cystic fibrosis. Seven cystic fibrosis and 59 normal amniotic fluids sampled between 17.5 and 18.5 gestational weeks were studied by radioimmunogel filtration, radioisotope technique, and isoelectric focusing chromatography. In normal amniotic fluid there was an increase of unsaturated B12-binding capacity from 16 to 41 weeks of gestation. There was no statistically significant difference in unsaturated B12-binding capacity, molecular weights and isoelectric points of haptocorrin, transcobalamin 2, and intrinsic factor between cystic fibrosis and normal amniotic fluid. Cobalamin-binding proteins study cannot help in the antenatal diagnosis of cystic fibrosis.

Amniotic Fluid↗
PubMed1982

Cobalamin-binding proteins in serum and saliva from patients with Sjögren's syndrome.

Cobalamin-binding proteins in saliva and in serum were determined in 28 patients with primary Sjögren's syndrome (primary SS), 8 patients with secondary SS and 20 matched healthy controls. The unsaturated transcobalamin II level in serum was significantly increased in patients with secondary SS. The unsaturated cobalamin binding capacity in saliva was increased in patients with primary SS. Considerable interindividual variations were found between patients and in the control group. The local production of cobalamin-binding proteins in SS was sufficient to achieve concentrations in saliva comparable to the control group. The cobalamin-binding capacity in saliva was significantly correlated to the albumin concentration in both primary and secondary SS patients, suggesting a defect in the aqueous phase.

Adult↗
PubMed1993

Induction of differentiation of myeloid leukemic cells by busulphan: in vivo and in vitro observations.

Treatment of a 74 year old patient with chronic myelogenous leukemia (CML) with busulphan resulted in an abrupt and pronounced decrease of the white blood cell (WBC) count with restoration of normal peripheral blood cell morphology and regression of splenomegaly. The Philadelphia positive (Ph+) clone was however still detectable. The alterations in the WBC count and morphology were not preceded by marrow hypoplasia but correlated closely with a marked decrease in the serum levels of Transcobalamin I (TC I), a vitamin B12-binding protein derived from immature myeloid precursors and a reciprocal rise in serum TC III, a vitamin B12-binding protein originating from terminally differentiated mature granulocytes. Studies on the HL-60 cell line showed that busulphan is capable of inducing leukemic cells to differentiate into granulocyte-like cells. These observations, taken together, suggest that in addition to its potent myelosuppressive effects, busulphan may induce apparent clinical remissions in some CML patients by promoting terminal cell differentiation.

Aged↗
PubMed1992

Serum B12 binding proteins versus seminal plasma binder.

It was well confirmed that B12 binding protein in human serum and body fluids largely consists of two kinds of binding proteins, physiologically B12 transporting transcobalamin and haptocorrins which does not involve in B12 transport. In seminal plasma, very potent B12 binding protein, in quantity as much as 23 times of normal serum, was identified. Separation characteristics, gel filtration, CM cellulose column chromatography and column IEF all agreed as one of the haptocorrins. One peculiar feature of seminal plasma binder is marked heterogeneity of much lower pI regions suggesting the presence of increased amount of sialic residues on the molecule. The preliminary data from this laboratory support the view, however, physiological role such as the relationship to the spermatogenesis is not known. The most recent findings in clinical observation on B12 is the treatment of male infertility using methycobalamin. The detailed analysis of seminal binders may open up new arena of B12 bioeffect.

Bacterial Outer Membrane Proteins↗
PubMed1975

Serum vitamin B12- binding proteins in neutropenia.

Serum unsaturated vitamin B12-binding capacity (UBBC) has been shown to fluctuate with neutrophil levels and has been reported to correlate with TBGP in normal and hyperleukocytic states. However, the present report demonstrates that the above relationship is not present in neutropenia, suggesting that some of our concepts regarding UBBC may have to be reexamined, since factors other than TBGP appear to be operative. There was a wide scatter of UBBC values among the 39 neutropenic subjects studied, the mean being significantly above normal. There were few low values. High UBBC was primarily confined to subjects with transient neutropenia. Normal values were generally seen in steady neutropenia. The difference in UBBC was primarily due to Transcobalamin I, the other serum binders being similar in both groups. No other significant diagnostic pattern of UBBC was found. Recovery from neutropenia was accompanied by a rise in UBBC in all cases except in four patients whose UBBC was initially very high and fell with recovery. No discernible pattern of serum B12 levels existed, although subnormal levels without evidence of B12 deficiency were found in three of the seven patients with aplastic anemia. Serum B12 levels did not change with recovery in approximately half of the neutropenic subjects, change being variable in the others. Neither serum B12, UBBC, total B12-binding capacity, or any of the three serum B12 binders correlated with neutrophil count, bone marrow findings, TBGP, or granulocyte turnover rate.

Agranulocytosis↗
PubMed1986

Methionine dependency of cultured human lymphocytes.

Human peripheral blood lymphocytes stimulated with phytohemagglutinin and a lymphocyte model consisting of the RPMI 6410 cell, a human virus-transformed B cell, required added methionine (Met) for growth of the cultures. This failure to meet all needs for Met via endogenous synthesis, which is characteristic of oncogenic transformation, occurred even in the presence of adequate homocysteine, methylfolate (5-CH3-H4PteGlu) and cobalamin (Cbl)-dependent methionine synthetase activity. Folinic acid (5-CHO-H4PteGlu), which provides available folate independently of Cbl, improved growth only slightly in the absence of Met. Free Cbl at 222 nM, an amount great enough to alter other intracellular events, failed to increase growth in the absence of Met, but 0.22 nM Cbl bound to transcobalamin II did, however, enhance growth.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1976

Protein-mediated uptake of vitamin B12 by isolated mitochondria.

Protein-mediated B12 uptake by isolated rat liver mitochondria has been shown to be enhanced by plasma transcobalamin (TC-II) but not by salivary R binder in vitro. The process is enhanced by calcium and depends on active mitochondrial respiration. Following uptake, cyanocobalamin is converted to adenosyl and methylcobalamins and released from the mitochondria. TC-II appears to be required for both cellular and mitochondrial uptake of vitamin B12.

Animals↗
PubMed1975

The role of vitamin B 12 and its transport globulins in the production of antibodies.

Immunological functions were repeatedly tested in a patient with hereditary deficiency of transcobalamin II (TC II): he was unable to synthesize immunoglobulins and specific antibodies, but was able to do so normally after injection of high doses of vitamin B 12 (1000 mug per week). Lymphocytes (B and T) were present in normal numbers prior to therapy, thus indicating normal differentiation of stem cells. In contrast, clonal expansion, necessary for immunoglobulin production, was possible only after vitamin B 12 administration. These observations, as well as the well known disturbances in haemopoiesis, indicate that vitamin B 12 is indispensable to rapidly replicating tissues, and that a severe deficiency of this vitamin in the cells can result from the absence of TC II.

Antibody Formation↗
PubMed1992

Effects of cobalamin, cobalamin analogues and cobalamin binding proteins on P388D1 mouse leukemic cells in culture.

Cobalamin-deficient P388D1 mouse leukemic cells were created by propagation in a cyanocobalamin-free medium in which the original fetal bovine serum was replaced by bovine serum albumin. These cobalamin-deficient cells gradually ceased to multiply when the medium contained 5-methyltetrahydrofolate. The growth of cells that had been cultured with this coenzyme was recovered following the addition of cyanocobalamin (CNCbl), at concentrations above 37 pM. In contrast to the effect of CNCbl, cobinamide, and cobalamin analogues prepared from hydroxy cobalamin by reaction with ascorbic acid, did not have a growth-inducing effect on these cells, nor did these analogues inhibit CNCbl-dependent growth. Transcobalamin II-cobalamin complex had a remarkably stimulating effect on cell growth. The growth inducing effect became apparent with a cobalamin concentration of only 0.37 pM. This was about 1/100th the level of free cobalamin required for cell growth. However, no growth-inducing effect was seen at an R protein-bound cobalamin concentration of 37 pM, indicating that once cobalamin has been bound to R protein, it loses its growth-promoting effect on these cells in culture.

Animals↗