The physiologic absorption of B12 (Cbl) in the body is mediated by a complex set of carrier proteins, receptors, and transporters before the dietary Cbl can be delivered for intracellular utilization.
① The Cbl uptake pathway starts when dietary Cbl, obtained through ingestion of animal foods such as meats, eggs, poultry, and dairy products, enters the stomach bound to animal proteins (P). ② Pepsin and hydrochloric acid (HCl) secreted in the stomach sever the animal food protein, releasing free Cbl.
③ Cbl is then immediately captured and bound to the R-protein Haptocorrin (R) produced by salivary glands of the oral cavity. This complex (Cbl-R) is transported from the stomach into the small intestine, where it is degraded ④ by proteases secreted by the pancreas (trypsin and chymotrypsin), again releasing free Cbl.
⑤ Cbl is then captured and bound by the protein Intrinsic Factor (IF). In man, IF is secreted into the gastric juice by the parietal cells of the stomach.
⑥ The cobalamin–intrinsic factor complex (Cbl-IF) travels to the distal ileum where it binds to cubilin, the receptor specific for Cbl-IF located on the microvilli of brush borders of ileal mucosa cells. The cubilin receptor shows specific binding with Cbl-IF, but not with free Cbl, free R, or free IF. Upon cubilin-mediated internalization of the Cbl-IF complex, intrinsic factor is degraded in the lysosome, which contains proteases that can attack the carrier protein (unlike the intestinal proteases).
⑦ After the initial attachment of Cbl-IF to the cubilin receptor there is a delay of 3 to 4 hours before Cbl, by itself, appears bound to haptocorrin (TC I) and transcobalamin (TC II or TC) in the portal bloodstream.
In the circulation, the amount of free Cbl is small. Approximately 80% of circulating Cbl is bound and carried on HC and 20% is bound and carried on TC. Cbl attached to TC is referred to as holo-transcobalamin (holoTC). HoloTC represents the biologically active fraction that is delivered to all tissues of the body.