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PubMed1995

Genomic structure of human transcobalamin II: comparison to human intrinsic factor and transcobalamin I.

Human transcobalamin II (TC II) gene was isolated and partially sequenced. The gene is composed of nine exons and eight introns spanning approximately 20 kb. Multiple potential transcription start sites were revealed by primer extension analysis. The 5'-flanking region of the gene contained no TATA-like motif, but a binding motif for HIP1, which is suggested to be important in the transcription of TATA-less housekeeping genes, was identified in a region very close to the initiator methionine codon. In addition, potential binding sites for a variety of transcription factors such as SP1, AP2, CF1, NF-IL6, Ets-1, Myb and E2A were also observed. Comparison of the genomic structure of TC II to other Cbl-binding proteins, human gastric intrinsic factor (IF) and transcobalamin I (TC I) revealed similar intron-exon organizations with respect to the number, position and size of exons. These results suggest that TC II, TC I and IF genes have originated by gene duplications of an ancestral gene and TC II, unlike the other two Cbl-binding proteins, is the product of a "housekeeping" gene.

Amino Acid Sequence↗
PubMed1990

Prevalence of intrinsic factor antibodies and vitamin B12 malabsorption in older patients admitted to a rehabilitation hospital.

It is possible that the commonly measured serum level of vitamin B12 may miss some cases when used to detect vitamin B12 malabsorption and deficiency in older persons. Serum levels of vitamin B12 and intrinsic factor antibody (IFAB) were determined on 250 consecutive patients over the age of 70 admitted to a rehabilitation hospital. Patients with abnormal results on either test were given the standard Schilling test when possible. Eight patients had documented B12 malabsorption. Of these, five had a low serum B12 level alone and one had a low serum B12 level and a positive IFAB level; however, two patients had positive IFAB and normal serum B12 levels. Serum IFAB level may serve as a useful adjunct to serum B12 level in detecting vitamin B12 malabsorption in older patients.

Aged↗
PubMed1963

INTRINSIC FACTOR.

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Chemical Phenomena↗
PubMed2001

Intrinsic factors involved in the depression of neuronal activity induced by temperature increase in rat hippocampal neurons.

The intrinsic factors involved in the temperature-dependent impairment of neuronal activity in hippocampal CA2-CA1 regions were investigated using optical recording techniques. At 32 degrees C, stimulation of the Schaffer collaterals in the hippocampal CA2 region evoked depolarizing optical responses that spread toward the CA1 region. The optical response was characterized by fast and slow components that were mainly related to the presynaptic action potentials and excitatory postsynaptic response, respectively. The increase of the temperature to 38 degrees C was associated with a reversible depression of the neuronal activity in the hippocampal brain preparations. The depression of neuronal activity was irreversible when the temperature was increased to 40 degrees C. In the presence of 22 mM glucose, the depression of the neuronal activity at 38 degrees C was significantly attenuated. Pyruvate (22 mM), but not lactate (22 mM), also improved the depression of neuronal activity induced by the temperature increase. Adenosine (200 microM) strongly depressed the excitatory postsynaptic response, but not presynaptic action potentials. 8-Cyclopentyl-1,3-dimethylxanthine (8-CPT) (10 microM), an adenosine A1 receptor blocker, attenuated the adenosine-induced depression of the excitatory postsynaptic response. 8-CPT (10 microM) prevented the impairment of the excitatory postsynaptic response induced by the increase of the temperature to 38 degrees C. In contrast, the depression of presynaptic action potential at 38 degrees C was not prevented by 8-CPT (10 microM). N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and methylcobalamin (10 microM), a vitamin B12 analogue, attenuated the inhibition of pre- and postsynaptic activities induced by the increase of the temperature to 38 degrees C. Glibenclamide, a KATP channel blocker, did not protect neuronal activity from the effects of the increase of the temperature. These results suggest that the heat-induced depression of neuronal activity is mediated by multiple factors, such as impairment of energy metabolism and increase in extracellular adenosine and nitric oxide (NO) levels in hippocampal neurons.

Adenosine↗
PubMed1985

Intrinsic factor within parietal cells of patients with juvenile pernicious anemia. A retrospective immunohistochemical study.

One of the diverse group of disorders that cause pernicious anemia in childhood, juvenile pernicious anemia, has been characterized by normal acid secretion, normal gastric mucosal histology, adequate intestinal absorption of cobalamin in the presence of exogenous gastric intrinsic factor (IF), but the inadequate "production" of IF from birth. Inadequate production has been inferred from the absence of measured IF in stimulated gastric secretions. To assess whether immunogenic IF was commonly present within the parietal cells of subjects with juvenile pernicious anemia, we studied paraffin-embedded biopsy material from the largest reported series of childhood pernicious anemia, using a well-characterized indirect immunoperoxidase method. Preliminary studies were able to identify IF in fundic mucosal biopsy specimens that had been stored for as long as 27 yr. In a blinded evaluation, six of the nine fundic biopsy specimens from children with juvenile pernicious anemia demonstrated immunogenic IF. Two sets of siblings were concordant for the presence or absence of intracellular IF, and six gastric biopsy specimens from patients with Imerslund's syndrome were all positive for IF. These findings indicate that juvenile pernicious anemia is a heterogeneous group of disorders whose similar clinical expression might be caused by (a) inadequate synthesis of IF, (b) a block in IF secretion, (c) the secretion of an abnormal IF that does not bind to cobalamin, or (d) the secretion of other abnormal IFs that could contain a number of other functional defects.

Anemia, Pernicious↗
PubMed1998

Expression of intrinsic factor and pepsinogen in the rat stomach identifies a subset of parietal cells.

Morphological and functional heterogeneity of parietal cells has been thought to be due to different maturation positions within the gastric gland. Morphodynamic studies have shown that 2% of parietal cells in mice derive from a pre-neck (chief) cell precursor. Intrinsic factor (IF) and pepsinogen, markers of rat chief cells, were used to determine if these proteins identified a subset of parietal cells that might reflect origin from the pre-neck cell lineage. The zymogenic region of the rat stomach and gradient-isolated fractions enriched in parietal and chief cells were fixed in 10% buffered Formalin or in Bouin's solution. Immunostaining was performed using indirect immunoperoxidase histochemistry and double-labeled immunofluorescence with antibodies raised against human IF, pepsinogen II, and H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase). In intact tissue, parietal (H(+)-K(+)-ATPase-positive) cells were found starting at the upper edge of the isthmus, but parietal cells positive for IF and pepsinogen were only found from just below the isthmus and neck region to the base of the gastric gland. Three to four percent of isolated parietal cells were positive for these ectopic markers. This subset of cells was also positive for H(+)-K(+)-ATPase. Thus products of rat chief cells are expressed in a subset of parietal cells. The percentage of positive cells is similar to that predicted to be derived from the pre-neck (chief) precursor lineage in the mouse. The distribution of these cells to the lower neck and base of the gland suggests that the expression of chief cell products is consistent with either predetermination by lineage or parietal cell maturation or with both processes.

Animals↗
PubMedDate not supplied

Effect of ethanol-generated free radicals on gastric intrinsic factor and glutathione.

The oxidation of acetaldehyde (generated from the metabolism of ethanol) by oxidases such as xanthine oxidase generates free radicals which can mobilize ferritin iron, alter hepatic glutathione and produce lipid peroxidation. The stomach, a site of ethanol metabolism and rich in xanthine oxidase, was studied with respect to the effects of ethanol on intrinsic factor (IF) binding of vitamin B-12 as well as gastric glutathione (GSH). Incubations of gastric homogenates with acetaldehyde-xanthine oxidase inhibited the B-12 binding ability by IF. A large acute dose of ethanol in vivo (5 g/kg, conc. greater than 40% w/v) decreased gastric IF binding of B-12 and depressed gastric GSH; these effects were markedly attenuated by the feeding of sodium tungstate which inhibited xanthine oxidase. Changes in B-12 binding paralleled changes in gastric GSH. Scatchard plots of IF binding of B-12 for homogenates suggested decreased number of binding sites rather than altered affinity. In conclusion, the gastric metabolism of ethanol generates free radicals which alter IF binding of B-12, depress gastric GSH and may play a role in alcohol-induced gastric injury.

Animals↗
PubMed1977

Purification of hog gastric intrinsic factor by a simple two-step procedure based on affinity chromatography and a selective guanidine hydrochloride gradient.

Monocarboxylic acid derivaties of vitamin B12 were covalently coupled to 1,6-hexanediamine-substituted Sepharose by using a water-soluble carbodiimide resulting in 1.32 micronmoles of B12 coupled per ml of Sepharose. After a source of crude hog intrinsic factor (IF) was passed over the column, a selective linear gradient of guanidine HC1 (0 to 4.0 M) was used to remove IF and 4.0 to 7.5 M to elute NIF (a vitamin B12-binding glycoprotein not active in promoting vitamin B12 absorption). Anti-IF antibodies blocked 99% of the B12 binding by the isolated IF and only 1% of the B12 binding by NIF. Passage over a hydroxyapatite column resulted in IF 99% pure with a specific activity of 29.8 microng of B12 binding per mg of protein. IF so isolated exhibited one homogeneous band on polyacrylamide gel electrophoresis and corrected B12 malabsorption in a patient with pernicious anemia.

Animals↗
PubMed1978

Racial patterns in pernicious anemia. Early age at onset and increased frequency of intrinsic-factor antibody in black women.

Pernicious anemia affects primarily elderly northern Europeans, but may affect others more often than previously thought. Therefore, we analyzed the data from 156 documented cases: there were 73 patients of "European" origin, 52 black patients and 31 Latin-American patients. The mean age (+/- 1 S.D.) at presentation among black women, 53 +/- 16 years, was lower than that of all the others (P less than 0.001 in most comparisons), and seven of the 33 black women were less than 40 years old. In addition, 23 of the 24 black women tested had circulating antibody to intrinsic factor. A similar though less striking antibody prevalence (85 per cent) and age pattern (60 +/- 13 years) in Latin-American women did not reach statistical significance. No other group exceeded the usual 55 to 70 per cent prevalence of antibody. These finding suggest a different form of or a different response to the disease in black women and perhaps in Latin-American women.

Adult↗
PubMed1982

Subtle cobalamin malabsorption in a vegan patient: evolution into classic pernicious anemia with anti-intrinsic factor antibody.

Classic pernicious anemia with abnormal Schilling test results developed in a previously described vegan patient who had coexisting subtle cobalamin malabsorption (demonstrable by abnormal ovalbumin-cobalamin absorption test results but normal Schilling test results). This suggests that the ovalbumin-cobalamin absorption test or a modified version may serve as a prodromal phenomenon to identify patients at risk for developing pernicious anemia. The patient's transformation was also accompanied by the appearance of serum anti-intrinsic factor antibody. A modified assay retrospectively detected this antibody a year earlier than did the standard assay, indicating that such modification enhances the sensitivity of this useful test.

Anemia, Pernicious↗
PubMed1975

[May the Schilling test be already repeated the next day using intrinsic factor?].

The effect of previous administration of a dose of 1000 mu-g vitamin B12 on the Schilling test was examined in 18 patients, repeating the test 24 hrs later. On the first day 57-Co was administered, while on the second day 58-Co labeled vitamin B12 was given. The counting error was less than 2.0% at the 95% confidence level. A decrease in urinary excretion of vitamin B12 of 28.7 plus or minus 22.2% (x plus or minus SD) was found. The mean difference between the two subsequent Schilling test series was statistically significant (p less than 0.05). The excretion data of the first and the second test correlate well (r = 0.86; p less than 0.01; y = 0.66 x + 1.09). Thus the repeated Schilling test with intrinsic factor must not be performed the next day.

Anemia, Pernicious↗
PubMed1997

Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor.

The disease is characterised by cobalamin (Cbl) deficiency in children 0-5 years old, causing failure to thrive, infections, megaloblastic anaemia, neuropathy, and mild general malabsorption; slight proteinuria is common. Cbl injections produce remission, but Cbl malabsorption and proteinuria persist. About 250 cases have been reported. Dogs also have it. The heredity is autosomal and recessive. The physiological and pathological absorption mechanisms are described: Cbl liberated from food by digestion is first bound to haptocorrin, but in the intestine it is transferred to intrinsic factor. In the ileum the complex attaches to a receptor on the enterocytes; this requires neutral pH and Ca2+. The receptor is a membrane-bound glycoprotein consisting of multiple subunits. The receptor-ligand complex is endocytosed and degraded in lysosomes, and the vitamin is transferred to transcobalamin which carries it to tissues. The same receptor is strongly expressed in the kidneys, but urine also contains its activity which can be assayed for diagnosis. The basic lesion is an error in the ileal receptor. In the affected dogs the synthesised receptor is retained intracellularly. Urine and ileal biopsies from human cases contained little receptor but it had conserved affinity for the ligand. Recently examined Arab patients did not excrete reduced amounts of the receptor. Apparently, the disease has subsets, such as different structural errors in the receptor and possibly faulty transport inside the enterocyte. The cause of the proteinuria is unknown but kidney damage due to severe Cbl deficiency and an error in a multiligand renal receptor are among the possibilities.

Animals↗
PubMed2002

Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin.

Changes in the absorbance spectrum of aquo-cobalamin (Cbl x OH(2)) revealed that its binding to transcobalamin (TC) is followed by slow conformational reorganization of the protein-ligand complex (Fedosov, S. N., Fedosova, N. U., Nexø, E., and Petersen, T. E. (2000) J. Biol. Chem. 275, 11791-11798). Two phases were also observed for TC when interacting with a Cbl-analogue cobinamide (Cbi), but not with other cobalamins. The slow phase had no relation to the ligand recognition, since both Cbl and Cbi bound rapidly and in one step to intrinsic factor (IF) and haptocorrin (HC), namely the proteins with different Cbl specificity. Spectral transformations observed for TC in the slow phase were similar to those upon histidine complexation with Cbl x OH(2) and Cbi. In contrast to a closed structure of TC x Cbl x OH(2), the analogous IF and HC complexes revealed accessibility of Cbl's upper face to the external reagents. The binders decreased sensitivity of adenosyl-Cbl (Cbl x Ado) to light in the range: free ligand, IF x, HC x, TC x Cbl x Ado. The spectrum of TC x Cbl small middle dotAdo differed from those of IF and HC and mimicked Cbl x Ado participating in catalysis. The above data suggest presence of a histidine-containing cap shielding the Cbl-binding site in TC. The cap coordinates to certain corrinoids and, possibly, produces an incapsulated Ado-radical when Cbl small middle dotAdo is bound.

Binding Sites↗
PubMed1990

[Postgastrectomy megaloblastic anemia--possible participation of anti-intrinsic factor antibody in its pathogenesis--report of a case].

A case of 78-year old man with megaloblastic anemia occurring 20 years after partial gastrectomy is reported. Since about 2 years earlier he had an episode of convulsion, and he had been on anti-convulsants (diphenylhydantion, phenobarbital) until admission. Physical examination revealed a pale lean man with polyneuropathy and mental impairment. Laboratory findings revealed WBC 3100/microliters, RBC 187 X 10(4)/microliters, HB 7.9 g/dl, MCV 124.4 microns3, MCH 42.7 micrograms, platelet counts 15.7 X 10(4)/microliters, serum vitamin B12 (VB12) 380 pg/ml, and serum folic acid 5.1 ng/ml. Serum autoantibodies to intrinsic factor (IF) and parietal cells were positive. Bone marrow examination revealed erythroid hyperplasia and megaloblastic changes. Schilling test revealed impaired absorption of VB12 with or without IF, but X-ray study of the small bowels was unremarkable. Treatment with intramuscular cyanocobalamin resulted in a rapid clinical improvement. A repeat Schilling test after 4 months of therapy showed a normal VB12 absorption in the presence of IF. These findings suggest that VB12 malabsorption of the 1st Schilling test was due to intestinal dysfunction caused by the VB12 deficiency state itself, and the improvement of VB12 absorption with IF after therapy suggests a pathogenesis similar to pernicious anemia in this patient.

Aged↗