Intrinsic factor and

Food vitamin B 2 appears to bind to a saUvary transport protein referred to as the R-protein, R-binder, or haptocorrin. In the stomach, R-protein and the intrinsic factor competitively bind the vitamin. Release from the R-protein occurs in the small intestine by the action of pancreatic proteases, leading to specific binding to the intrinsic factor. The resultant complex is transported to the ileum where it is bound to a cell surface receptor and enters the intestinal cell. The vitamin is then freed from the intrinsic factor and bound to transcobalamin II in the enterocyte. The resulting complex enters the portal circulation. 

Shaw, S., Herbert, V., Colman, N. and Jayatilleke, E. (1990). Effect of ethanol-generated free radicals on gastric intrinsic factor and glutathione. Alcohol 7, 153-157. 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

Facilitated transport is essentially the same as carrier-mediated transport, except that besides a carrier molecule, another transport facilitator is essential. For example, vitamin B12 attaches to the intrinsic factor, and the vitamin B12-intrinsic factor complex then attaches to the carrier molecule and is transported. This transport process does not require energy and does not proceed against a concentration gradient (Figure 1.3). 

Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B,2 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin Bi2 malabsorption due to defects of the receptor sites in the distal ileum. 

Once a chemical enters the body of animal or human, it undergoes metabolic reaction. A host of factors modulate the reaction rate and the induction of toxicological effects. These factors have been termed intrinsic factors and include animal species, gender, age, nutritional status, pregnancy, other health status, and circadian rhythms. In addition, there are certain extrinsic factors (e.g., physicochemical properties of chemicals, solvent or vehicle, route of exposure, temperature, and humidity) during exposure to chemicals that also influence the effect of a test chemical. We shall discuss these factors in greater detail. 

B21. Brugge, W. R., Goff, J. S., Allen, N. C., Podell, E. R., and Allen, R. H., Development of a dual label Schilling test for pancreatic exocrine function based on the differential absorption of cobalamin bound to intrinsic factor and R protein. Gastroenterology 78, 937-949 (1980). 

Gl. Grasbeck, R., Intrinsic factor and other vitamin B12 binding proteins. In Progress in... 

H6. Hippe, E., Haber, E., and Olsen, H., Nature of vitamin B12 binding. II. Steric orientation of vitamin B12 on binding and number of combining sites of human intrinsic factor and the transcobalamins. Biochim. Biophys. Acta 243, 75-82 (1971). 

Zl. Zacharalds, R., Muir, M., and Chanarin, I., Comparison of serum vitamin B12 estimation by saturation analysis with intrinsic factor and with R-protein as binding agents. J. Clin. Pathol. 34, 357-360 (1981). 

Another approach is to measure the redox potential at different temperatures and to calculate AH° and AS0. However, these thermodynamic terms also depends on both protein intrinsic factors and solvent reorganization effects. In general, the... 

As reviewed recently by Solomons W, many dietary and non-dietary factors may affect the bloavallablllty of zinc. Dietary factors are subdivided Into "Intrinsic factors" and "extrinsic factors". "Intrinsic factors" relate to the chemical nature of zinc Itself. "Extrinsic factors" Include non-heme Iron, ethyl-enedlamlnetetraacetlc acid (EDTA), dietary fiber, phytic acid, calcium, copper and specific foods such as cow s milk, cheese, coffee, eggs, celery and lemon which have been demonstrated to decrease zinc bloavallablllty as well as other factors which may Increase zinc utilization. 

Within the ileal mucosal cell, the vitamin is released by lysosomal proteolysis of intrinsic factor, and is bound to transcobalamin II, a vitamin B12 binding protein synthesized in the enterocytes. Transcobalamin II is in vesicles destined for export from the enterocytes, and it is assumed that vitamin B12 binds to the apoprotein in these vesicles rather than in the lysosomes, because otherwise newly synthesized transcobalamin would be hydrolyzed by lysosomal proteases (Seetharam, 1999). 

About 70% of patients also have antiintrinsic factor antibodies in plasma, saliva, and gastric juice. These canbe either blocking antibodies, which prevent the binding of vitamin B12 to intrinsic factor, or precipitating antibodies, which precipitate both free intrinsic factor and intrinsic factor-vitamin B12 complex. Some patients have both types of antiintrinsic factor antibody. Although the oral administration of partially purified preparations of intrinsic factor will restore the absorption of vitamin B12 in many patients withpernicious anemia, this can eventually result in the production of antiintrinsic factor antibodies, so parenteral administration of vitamin B12 is the preferred means of treatment. 

The test can be repeated, giving intrinsic factor orally together with the radioactive vitamin B12 - if the impaired absorption was because of a simple lack of intrinsic factor, and not to antiintrinsic factor antibodies in saliva or gastric juice, then a normal amount of the radioactive material should be absorbed and excreted. 

A9a. Ardeman, S., and Chanarin, I., A method for the assay of human gastric intrinsic factor and for the detection and titration of antibodies against intrinsic factor. Lancet 2, 1350-1354 (1963). 

C6. Castle, W. B., Development of knowledge concerning the gastric intrinsic factor and its relation to pernicious anemia. New Engl. J. Med. 249, 603-614 (1953). 

C14. Castro-Curel, Z., and Glass, G. B. J., Fractionation of intrinsic factor and proteolytic enzymes of human gastric mucosa on DEAE-cellulose column. Federation Proc. 23, 439 (1964). Abstr. 

G14. Glass, G. B. J., Localization of intrinsic factor and the sites of B g binding in the paper electrophoresis of human gastric juices and concentrates from hog gastric mucosa. Haematol. Latina Milan 2, 231-240 (1959). 

G62a. Grasbeck, R., Simons, K., and Sinkkonen, I., Purification of intrinsic factor and vitamin Bjg binders from human gastric juice. Ann. Med. Exptl. Biol. Fenniae (Helsinki) SuppL 40, No. 6, 1-24 (1962). 

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