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Absorption and metabolism of vitamin B12
Very small amounts of vitamin B12 can be absorbed by passive diffusion across the intestinal mucosa, but under normal conditions this is insignificant; the major route of vitamin B12 absorption is by attach-ment to a specific binding protein in the intestinal lumen.
This binding protein is intrinsic factor, so called because in the early studies of pernicious anemia it was found that two curative factors were involved: an extrinsic or dietary factor, which is now known to be vitamin B12, and an intrinsic or endogenously pro-duced factor. Intrinsic factor is a small glycoprotein secreted by the parietal cells of the gastric mucosa, which also secrete hydrochloric acid .
Gastric acid and pepsin play a role in vitamin B12 nutrition, serving to release the vitamin from protein binding, so making it available. Atrophic gastritis is a relatively common problem of advancing age; in the early stages there is failure of acid secretion but more or less normal secretion of intrinsic factor. This can result in vitamin B12 depletion due to failure to release the vitamin from dietary proteins, although the absorption of free vitamin B12 (as in supplements or fortified foods) is unaffected. In the stomach, vitamin B12 binds to cobalophilin, a binding protein secreted in the saliva.
In the duodenum cobalophilin is hydrolyzed, releasing vitamin B12 to bind to intrinsic factor. Pan-creatic insufficiency can therefore be a factor in the development of vitamin B12 deficiency, since failure to hydrolyze cobalophilin will result in the excretion of cobalophilin-bound vitamin B12 rather than transfer to intrinsic factor. Intrinsic factor binds the various vitamin B12 vitamers, but not other corrinoids.
Vitamin B12 is absorbed from the distal third of the ileum. There are intrinsic factor–vitamin B12 binding sites on the brush border of the mucosal cells in this region; neither free intrinsic factor nor free vitamin B12 interacts with these receptors.
In plasma, vitamin B12 circulates bound to transco-balamin I, which is required for tissue uptake of the vitamin, and transcobalamin II, which seems to be a storage form of the vitamin.
There is a considerable enterohepatic circulation of vitamin B12. A third plasma vitamin B12 binding protein, transcobalamin III, is rapidly cleared by the liver, with a plasma half-life of the order of 5 min. This provides a mechanism for returning vitamin B12 and its metabolites from peripheral tissues to the liver, as well as for clearance of other corrinoids without vitamin activity, which may arise from either foods or the products of intestinal bacterial action, and be absorbed passively across the lower gut.
These corrinoids are then secreted into the bile, bound to cobalophilins; 3–8 μg (2.25–6 nmol) of vitamin B12 may be secreted in the bile each day, about the same as the dietary intake. Like dietary vitamin B12 bound to salivary cobalophilin, the biliary coba-lophilins are hydrolyzed in the duodenum, and the vitamin binds to intrinsic factor, so permitting reab-sorption in the ileum. Although cobalophilins and transcorrin III have low specificity, and will bind a variety of corrinoids, intrinsic factor binds only cobalamins, and so only the biologically active vitamin is reabsorbed.
There are three vitamin B12-dependent enzymes in human tissues: methylmalonyl-CoA mutase (dis-cussed below under methylmalonic aciduria), leucine amino-mutase, and methionine synthetase.
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