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PubMed1977

Inhibition of vitamin B12 binding to transcobalamin II at low pH: basis of a procedure for quantitation of circulating TC II and R binders.

A diminution in the binding of exogenous vitamin B12 by serum or plasma at pH 1.5 to 2 (acid-resistant binding capacity, ARBC) as compared with the binding capacity at neutral pH (unsaturated vitamin B12 binding capacity, UBBC) was observed. This phenomenon was found to be attributable to the absence of transcobalamin II (TC II)-associated vitamin B12 from serum labeled at low pH, as demonstrated by gel chromatography on Sephadex G-200. Further confirmation was obtained by demonstration of a significant correlation between the ARBC and the R binder content, quantitated as resistance to precipitation by ammonium sulfate at a 2M concentration. Serum labeled at acid pH failed to deliver vitamin B12 to Hela cells indicating absence of a "functional" TC II-B12 complex. The differing vitamin B12 binding capacities of neutral and acidified material was utilized to fractionate the unsaturated vitamin B12-binding proteins of serum and plasma. The ARBC was used to measure the R binder content, and TC II was calculated from the difference between UBBC and ARBC. The fractionation procedure was performed on 75 sera and showed increased ARBC in patients with myeloproliferative disorders and decreased ARBC in leukopenia. The content of unsaturated vitamin B12-binding protein was compared in 75 paired samples of serum and plasma collected from EDTA-anticoagulated blood containing sodium fluoride to inhibit release of granulocyte binders. The ARBC content of fluoridated plasma was significantly lower, due to decreased in vitro R binder release. Plasma also contained less TC II, possibly related to in vitro cellular uptake of this binder in fluoridated plasma.

Blood Proteins↗
PubMed2002

Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study.

BACKGROUND: We examined the effect of oral vitamin B(12) treatment on fluctuations in plasma total cobalamin and its binding proteins transcobalamin (TC) and haptocorrin (HC). METHODS: Patients (n = 88; age range, 38-80 years) undergoing coronary angiography (part of the homocysteine-lowering Western Norway B-Vitamin Intervention Trial) were allocated to daily oral treatment with (a) vitamin B(12) (0.4 mg), folic acid (0.8 mg), and vitamin B(6) (40 mg); (b) vitamin B(12) and folic acid; (c) vitamin B(6); or (d) placebo. EDTA blood was obtained before treatment and 3, 14, 28, and 84 days thereafter. RESULTS: The intraindividual variation for patients not treated with B(12) was approximately 10% for plasma total cobalamin, total TC, apo-TC, and apo-HC, and <20% for holo-TC and TC saturation. In B(12)-treated patients, the maximum change in concentrations was observed already after 3 days for total TC (-16%), holo-TC (+54%), and TC saturation (+82%). At this time holo-HC (+20%) and plasma total cobalamin (+28%) showed an initial burst, but had increased further at 84 days. All changes were highly significant compared with the control group (P <0.0001). CONCLUSIONS: Oral vitamin B(12) treatment produces maximal effects on total TC, holo-TC, and TC saturation within 3 days, whereas maximal increases in holo-HC and plasma total cobalamin occur later. The results support the view that holo-TC is an early marker of changes in cobalamin homeostasis.

Adult↗
PubMed2002

Cobalamin pseudodeficiency due to a transcobalamin I deficiency.

Cobalamin (vitamin B12) deficiency warrants appropriate evaluation because cobalamin is necessary in certain biochemical functions. R-binder deficiency, which causes low cobalamin levels, is a rare and benign pseudodeficiency. If not further evaluated by determining levels of methylmalonic acid and homocysteine, however, such a patient would be given unneeded treatment. We report a case in which a patient has an R-binder deficiency, specifically transcobalamin I deficiency, with a low vitamin B12 level but no true vitamin B12 deficiency.

Deficiency Diseases↗
PubMed1977

A simple method for the separate measurement of transcobalamins I, II, and III: normal ranges in serum and plasma in men and women.

A simple method for the separate measurement of the unsaturated binding capacity of the three main circulating vitamin B12 binders, transcobalamins (TCs) I, II, and III, is described. The method involves batch separation of TC I and III from TC II by means of Quso G32, followed by batch separation of TC I from TC II with the use of diethylaminoethyl. The present study provides the first complete comparison of unsaturated TC I, II, and III in serum versus fluoridinated plasma of a single group of normal men versus women. There are consistently higher values in serum, largely due to an in vitro increment of TC III, prevented by NaF. The results are compared with values for some of these parameters obtained by others with the use of different methods, providing a standard for evaluating significance of results by various methods.

Adult↗
PubMed1990

Human umbilical vein endothelial cells secrete transcobalamin II.

Transcobalamin II (TC II) is essential for cellular uptake of cobalamin. However, the origin of this transport protein is controversial and many organ sources have been suggested. We studied human umbilical vein endothelial cells cultured in vitro. The cells contained TC II (2.3 pmol/10(8) cells) and released progressively increasing amounts of the protein into the surrounding medium during the 3-day incubation period. This release exceeded the starting intracellular content of TC II. In contrast, endothelial cells did not contain or elaborate R binder, the other major circulating binding protein for cobalamin, Cycloheximide inhibited the elaboration of TC II, suggesting that the endothelial cells synthesize the protein. Thrombin, which stimulates tissue plasminogen activator release, did not enhance TC II release, and neither did endotoxin or mellitin. However, thrombin did appear to partially protect TC II release from inhibition by cycloheximide. Among other cells studied, human fibroblasts also released TC II into the incubation medium, while K562 human leukemia cells, ARH-77 and HS Sultan human plasma cell lines, and Raji strain lymphoblasts did not. The data suggest that endothelial cells are an important source of the metabolically crucial TC II.

Cycloheximide↗
PubMed1989

[Quantitative evaluation of the surface membrane receptors of leukemic cells to blood serum transcobalamin-II].

Serum protein transcobalamin II (TC-II) is responsible for transport of cobalamins into mammalian cells. A method of quantitative estimation of plasma membrane receptors of hemopoietic cells to TC-II cobalamin complex is suggested. Analysis of mouse leukemia L1210 cells includes the saturation of radiolabelled ligand-receptor complex with papain. The number of receptors and 57CoCNCbl content in one cell is determined by differentiated radioactivity count of solubilized protein complexes and of cytoplasm.

Animals↗
PubMed1989

[Megaloblastic anemia caused by a congenital deficiency of transcobalamin II. Apropos of a new case].

Megaloblastic anaemia is very rare in the first weeks of life and it is related to impaired metabolism of folic acid or vitamin B12. One of this disorders is the congenital transcobalamin II deficiency. The case of a three month old infant, with vomiting, diarrhoea and severe anaemia is presented. Both parents and the child had very low or undetectable levels of serum TC II, respectively. Using i.m. hydroxycobalamin at high doses, the clinical and laboratory responses have been satisfactory.

Anemia, Macrocytic↗
PubMed1989

Cobalamin-binding capacity of haptocorrin and transcobalamin: age-correlated reference intervals and values from patients.

Unsaturated cobalamin-binding capacity in plasma (P-UBBC) is determined by use of a silica gel (QUSO G32) to separate haptocorrin (P-ApoHC) and transcobalamin (P-ApoTC). The method is sensitive and precise: detection limit 13 pmol/L, interassay coefficients of variation 3% for P-UBBC (mean = 1080 pmol/L), 4% for P-ApoTC (mean = 700 pmol/L) (n = 30). Values for P-UBBC, P-ApoHC, P-ApoTC, and P-TBBC (P-UBBC plus P-cobalamin) determined in a population study of 228 individuals, ages 21-87 years, did not differ by sex. These values increased with age, whereas the cobalamin saturation (P-cobalamin as percentage of P-TBBC) decreased with age. However, these changes were statistically significant but marginal and thus not clinically important. We therefore suggest using combined reference intervals (central 95 percentiles) for all age groups: 500-1200 pmol/L for P-UBBC, 90-275 pmol/L for P-ApoHC, 400-930 pmol/L for P-ApoTC, 850-1600 pmol/L for P-TBBC, and 20-50% for cobalamin saturation. Results for 277 inpatients show high P-ApoHC in myeloproliferative disorders or acute nonlymphatic leukemia, whereas P-ApoTC concentrations are high in some patients with lymphoproliferative disorders or autoimmune diseases.

Adult↗
PubMed1989

Structure of the cDNA encoding transcobalamin I, a neutrophil granule protein.

Transcobalamin I (TCI) is a member of the R binder family of vitamin B12 binding proteins. It is a major protein constituent of secondary granules in neutrophils. We have isolated and characterized full length cDNA clones encoding TCI in order to determine whether its expression is coordinately regulated with the appearance of secondary granules and whether it is consequently a useful marker of granulocyte development. Partial amino acid sequences of human R protein were obtained from tryptic digestion fragments. Using the polymerase chain reaction, a partial TCI cDNA probe was isolated by selective amplification of a region of cDNA located between two oligonucleotides deduced from the available partial amino acid sequences. The amplified probe was then used to obtain full length clones from a granulocyte cDNA library. Identity of the clones was confirmed by matching DNA sequence to known peptide amino acid sequence. TCI is transcribed to a single 1.5-kilobase mRNA species. The predicted protein sequence is 433 amino acids long. We have compared the sequence of TCI to that of rat intrinsic factor. The two proteins have areas of extensive homology which implicate regions potentially important for vitamin B12 binding. TCI mRNA was present in late neutrophil precursors but absent from uninduced and induced HL60 cells.

Amino Acid Sequence↗
PubMed1985

Receptor distribution and the endothelial uptake of transcobalamin II in liver cell suspensions.

To determine the nature of binding of transcobalamin II (TC-II) to liver cells, we covalently coupled purified holo-TC-II to submicron latex minibeads using glutaraldehyde. Incubation of the probe with liver cell suspensions at 4 degrees C led to its binding by endothelial cells but not by hepatocytes or Kupffer cells, as visualized by scanning electron microscopy. At 37 degrees C, the probe was internalized by the endothelium through a system of coated pits and vesicles as shown by transmission electron microscopy. Inhibition studies by pre-incubation with excess native TC-II demonstrated the specificity of binding. Fractionation of these cell suspensions on metrizamide gradients yielded large cell (hepatocyte-rich) and small cell (endothelium-rich) fractions. The binding of the minibead probe occurred again exclusively on endothelial cells in the small cell fraction. 125I-labeled holo-TC-II also bound to the small cell but not to the large cell fraction. Binding was saturable (Ka, 0.225 X 10(9) mol/L-1) and receptor number was calculated to be 1.33 X 10(3) per cell. Time-dependent incubation of 125I-labeled TC-II with the endothelium-rich fraction led to its uptake, reaching a steady-state plateau at 4 degrees C. At 37 degrees C, however, the initial uptake was followed by gradual release of the label into the medium. We conclude that in the liver, holo-TC-II binds initially to endothelium, where it is internalized and is subsequently released probably to the interstitial space. Thus, the endothelium may play a fundamental role in the regulation of the uptake of TC-II by the liver.

Animals↗
PubMed1979

[Granulocyte dysfunction in transcobalamin II deficiency].

Granulocytes from a boy with congenital transcobalamin II (TC II) deficiency were found to have abnormally low antibacterial activity against Staphylococcus aureus. Transfusion of normal plasma supplemented with hydroxocobalamin temporarily restored granulocyte bactericidal activity to normal. Granulocyte function was also temporarily restored by oral leucovorin. The defect appears to be causally related to the patient's TC II deficiency and indirectly to an intracellular deficiency of cobalamin and folate coenzymes [1].

Blood Bactericidal Activity↗
PubMed1986

Purification and molecular characterization of human transcobalamin II.

Transcobalamin II (TCII) has been purified from Cohn fraction III of human plasma by batchwise binding to and then elution from carboxymethyl-Sephadex, affinity chromatography using photo-labile aminopropyl cobalamin coupled to activated Sephacryl S-200, and finally chromatography through carboxymethyl cellulose. The yield was approximately 80%. The addition of protease inhibitors in all steps of the purification procedure and extensive washing of the carboxymethyl-Sephadex prior to eluting the TCII minimized degradation of the protein and the final preparation of holo-TCII contained 1 mol of cobalamin/mol of protein. A single polypeptide of 43,000 daltons was obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The NH2-terminal 19 amino acids have been determined for human TCII. 12 of the amino acids are homologous with rabbit TCII and six are homologous with human R-binder, but there is no homology with human intrinsic factor.

Amino Acid Sequence↗
PubMed1985

Homozygous transcobalamin II deficiency maintained on oral hydroxocobalamin.

A case of transcobalamin II (TCII) deficiency in which a total absence of TCII was demonstrated both functionally and immunologically is reported. Unlike previously described patients, this child has been maintained on oral hydroxocobalamin, 2 mg daily, without any parenteral supplementation for the last five years. At the age of six years her development is normal and her health is good. Plasma cobalamin levels are in the range of 3,000 ng/L and most of this appears to be bound to a molecule, which on gel filtration, elutes with albumin. In an extended family study, a clear separation of heterozygotes from both the propositus and from normal subjects suggests that the underlying defect in this condition is confined to a single gene.

Administration, Oral↗
PubMed1979

[Transcobalamine-II-polymorphism: biochemical and clinical aspects of rare variants].

Transcobalamin II(TC II) is an essential transport protein for vitamin B12 in blood. TC II can be split up into isoproteins by polyacrylamide gel electrophoresis. Family studies are compatible with a genetic polymorphism of TC II and a five allele system. Screening of TC II isoprotein patterns in about 1000 individuals yielded two unusual TC II variants: The first case was a black female with severe megaloblastic anemia since infancy. Her TC II was elevated and bound B12, but displayed markedly diminished functional capacity to transfer radioactive cyanocobalamin in cellular systems. Comparison of this patient's TC II isoprotein pattern with known variants showed a distinct difference in electrophoretic mobility, indicating the presence of a sixth allele. The second patient, also presenting with pernicious anemia-like symptoms, was found to possess an unusual TC II variant with reduced TC II serum levels. Corresponding variants were also observed in the patient's asymptomatic children. Thus, abnormal TC II variants probably causing megaloblastic anemias both correlated with unusual isoprotein patterns.

Anemia, Megaloblastic↗
PubMed1982

The influence of phagocytosis on transcobalamins releasing from polymorphonuclear granulocytes of patients with Hodgkin's disease.

The release of transcobalamins I and III (TC-I/III) during phagocytosis of latex particles from polymorphonuclear granulocytes of healthy persons and patients with Hodgkin's disease were studied. Our investigations indicate that phagocytosis stimulates the release of these proteins in both examined groups. The values of the patients with I and II stage of disease did not differ distinctly from the results of healthy persons. This preliminary studies will be extended to patients with advanced Hodgkin's disease. In addition, our results may suggest the influence of phagocytosis on the activation of TC-I/III synthesis.

Blood Proteins↗
PubMed1983

[Transcobalamin II dynamics in a plasma turnover study of patients with lupus erythematosus. Preliminary report].

Increased serum levels of the essential vitamin B12 binding protein, transcobalamin II (TC2) were previously observed in autoimmune disease. The periods of raised serum level correlated with clinical disease activity in patients with SLE and dermatomyositis. The correlation of serum levels with disease activity in a large group of 44 Swiss SLE patients was shown to be most reliable for TC2, when compared to certain established serological markers such as complement factors C3 and C4, antinuclear antibody titer or antinative DNA antibodies. Several questions were raised: Why is the TC2 level elevated in active SLE? Is the accumulation in serum due to lack of TC2 uptake by the cell or is it due to stimulation of synthesis? Answers were sought by applying a plasma turnover test for TC2 to the SLE patients. After 400 ng/kg cyanocobalamin (i.m.) the TC2 level decreased, due to preferential uptake of holo TC2 by the cells. Total TC2 levels were determined by radioimmunoassay. Normalisation of the plasma level and corresponding reappearance of apo TC2 was interpreted as newly synthesized TC2. Twelve SLE patients and six healthy controls were investigated. One SLE patient was treated with a higher cobalamin dose (200 micrograms) to ensure complete saturation of TC2. The TC2 level decrease after cobalamin injection was comparable in controls and patients, independently of the state of the disease. Normalisation of plasma levels was significantly faster, elevation above starting levels was observed, in 3 of 5 SLE patients exhibiting active disease. In the remaining 9 patients normalisation of the plasma level was comparable to the control group. Our conclusions are that TC2 uptake, in other words TC2 consumption by the cell, is unchanged in SLE, and that an increased rate of TC2 synthesis may be the cause of elevated plasma levels in active SLE.

Autoimmune Diseases↗
PubMed1984

Distribution of genetic variants of transcobalamin II in Nigerian black populations.

Transcobalamin II ( TC2 ) phenotyping was performed in Nigerian black males from several ethnic groups, using polyacrylamide gel electrophoresis in combination with autoradiography. The TC2 gene frequencies in the total Nigerian sample amounted to .064 (X), .124 (S), .498 (M), and .313 (F). Compared to white populations, the frequency of TC2 *X is low while the frequencies of TC2 *S and TC2 *F are high, which confirms previous studies on blacks. In some of the rare phenotypes we found, in addition to common TC2 variants, TC2 gene products with an electrophoretic mobility intermediary to X and S, and to M and F, indicative of further microheterogeneity in the genetic system of TC2 . The TC2 gene frequency data indicate interpopulation heterogeneity for this marker. Major differences were found between the Sudan and Guinea Savanna Group ( SGSG ) and the Middle Belt Group, and between the SGSG and the Ibos . The results of our comparative study confirm to some extent similar surveys, which have been based on the distribution of the ABO blood groups.

Autoradiography↗
PubMed1983

Genetic evidence for fetal origin of transcobalamin II in human cord blood.

Phenotypes of transcobalamin II (TC2) were determined in 95 maternal-cord serum pairs in order to identify the origin of TC2 in human cord blood. Unsaturated (apo) TC2 in serum was labeled with radioactive (57Co) cobalamin (CbI) and separated into isoproteins by polyacrylamide gel electrophoresis and autoradiography. Discordancy between the maternal and the cord serum type was observed in 45% of the pairs. The results demonstrated that, at the end of pregnancy, the fetus is capable of TC2 synthesis and that there is no detectable transplacental passage of maternal apo-TC2. Presence of maternal saturated (holo) TC2 in cord serum could be excluded in 9 informative discordant pairs by exchanging endogenously bound CbI with 57Co-CbI. Our finding that TC2 in human cord serum is of fetal rather than maternal origin suggests an essential role for fetal TC2 in CbI utilization and appears to contradict the hypothesis that transplacental passage of maternal TC2 may explain the normal fetal development in cases of congenital TC2 deficiency. The total immunoreactive TC2 content in 23 maternal serum samples collected at the end of pregnancy (812 +/- 175 pM CbI equivalent) was significantly higher than in the corresponding cord sera (605 +/- 148 pM; p less than 0.001) and did not significantly differ from the value in a control group of healthy male and female adults (841 +/- 192 pM). At the end of pregnancy, the apo-TC2 content in 12 maternal serum samples (760 +/- 347 pM) was significantly higher than in the corresponding cord sera (501 +/- 254 pM; p less than 0.05) and did not significantly differ from the value in the control group (747 +/- 137 pM).

Blood Proteins↗