Absorption and Transport of Cobalamin (Vitamin B12)

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Annual Reviewswww.annualreviews.org/aronline362 SEETHARAM & ALPERSAnnu. Rev. Nutr. 1982.2:343-369. Downloaded from arjournals.annualreviews.orgby Hebrew University of Jerusalem on 11/18/08. For personal use only.can interfere with the serum assay. This is especially true since the commerciallyprepared binding proteins contain some R protein rather than 100%intrinsic factor. Cobalamin analogs bind more avidly to R proteins than tointrinsic factor. Therefore cobalamin deficiency can be masked by the presenceof analogs in the serum resulting in a falsely normal serum value (100).As many as 20% of cobalamin deficient patients might be mistaken in thisway. If suspicion still exists that deficiency is present, the microbiologicalassay should be used to confirm this diagnosis.Further problems with the serum vitamin B12 assay have been noted (48).These levels can be low when the patient has normal body stores. Thirtypercent of patients with folate deficiency have low serum vitamin B12 levels,though the reason is not clear. Protein deficiency will lower the amount oftotal serum vitamin B~2 without having much effect on delivery of cobalaminto tissues, because most of the vitamin BI2 binding activity in serumis due to transcobaiamin I. Up to 75% of strict vegetarians have low serumcobalamin levels without evidence of deficiency (28). It is likely that thesepatients would develop some signs of anemia with continued inadequateintake. Finally, in pregnancy serum vitamin B12 level is low due to dilutionand redistribution of the binding proteins. Less than 120 pg/ml of vitaminB~2 is associated with low body stores if the above factors are not present.High levels of vitamin B12 (> 1000 pg/ml) are seen with acute liverdisease due to release from the hepatocytes, and with increased white cells,since they produce an R protein that increases the total serum vitaminB12 binding capacity.ACKNOWLEDGMENTSWe sincerely thank Mrs. Catherine Camp for superb secretarial help inpreparation of the manuscript. We also thank Ms. Marlene Jimenez for herassistance in proofreading and other help. Part of the work by the authorscontained in this review was supported by grants AM 14038 and AM26638,both from the National Institutes of Health.Literature Cited1. Addison, T. 1855. On the Constitutionaland Local Effects of Disease of the SuprarenalCapsule~ London: S. Highley.pp. 2-42. Alien, R. H. 1975. Human vitamin Bt2transport proteins. Prog. Hematol. 9:57-843. Mien, R. H., Majerus, P. W. 1972.Isolation of vitamin Bt2 binding proteinsusing affinity chromatography. LPreparation and properties of vitaminBt2-sepharose. Z BioL Chem.247:7695-7014. Allen, R. H., Majerus, P. W. 1972. Isolationof vitamin Bt2 binding proteinsusing affmity chromatography. III. Puriticationand properties of humanplasma transcobalamin II. d. Biol.Chem. 247:7709-175. Allen, R. H., Mehlman, C. S. 1973. Isolationof gastric vitamin Btz-bindingproteins using affinity chromatography.I. Purification and properties of human
Hoflbrand, A. V. 1978. Evidence for intestinalorigin of transeobalamin II dur-Annual Reviewswww.annualreviews.org/aronlineCOBALAMIN ABSORPTION & TRANSPORT 363Annu. Rev. Nutr. 1982.2:343-369. Downloaded from arjournals.annualreviews.orgby Hebrew University of Jerusalem on 11/18/08. For personal use only.intrinsic factor. Z Biol. Chem. 248:3660-696. Allen, R. H., Mehlman, C. S. 1973. Isolationand properties of hog intrinsicfactor and hog nonintrinsic factor. J.Biol. Chern. 248:3670-807. Allen, R. H., Seetharam, B., Podell, E.,Alpers, D. H. 1978. Effect ofproteolyticenzymes on the binding of cobalamin toR protein and intrinsic factor. J.. Clit~Invest. 61:47-538. Allen, R. H., Seetharam, B., Allen, N.C., Podell, E., Alpers, D. H. 1978. Correctionof cobalamin malabsorption inpancreatic insufficiency with a cobalaminanalogue that binds with highaffinity R protein but not to intrinsicfactor. J. Clin. lnvest. 61:1628-349. Andersen, K. J., Von der Lippe, G.1979. The effect of proteolytic enzymeson the vitamin Bt2-binding proteins ofhuman J. Gastroent. gastric juice 14:833-38 and saliva. Scand.10. Anderson, R. G. W., Goldstein, J. L.,Brown, M. S. 1977. A mutation thatimpairs the ability of lipoprotein receptorsto localize in coated pits on the cellsurface of human fibroblasts. Nature270:695-9911. Ardeman, S., Chanarin, I. 1965. Stimulationof gastric intrinsic factor .secretion.Br. Med. J. 1:1417-1812. Ashwell, G., Morell, A. G. 1974. Therole of surface carbohydrates in thehepatic recognition and transport of circulatingglycoproteins. Adv. Enzymol.41:99-12813. Baker, S. J. 1967. Human vitamindeficiency. World Rev. Nutr. Diet. 8:62-12614. Begley, J. A., Morelli, T. A., Hall, C. A.1977. Bn bindingproteins after injectionof eyanocobalamin. N. EngL J.Med. 297:614-15.15. Bertcher, R. W., Meyer, L. M., Miller,I. F. 1958. Co ~° vitamin B~2 binding capacityof normal human saliva. Proc.Soc. Exp. Biol. Med. 99:513-1516. Binder, H. J., Donaldson, R. M. 1978.Effect of cimetidine on intrinsic factorandpepsin secretion in man. Gastroenterology74:371-7517. Booth, C. C., Mollin, D. L. 1957. Importanceof the ileum in the absorptionof vitamin B12. Lancet 2:100717a. Bozian, R. C., Ferguson, J. L., Heyssel,R. M., Meneely, G. R., Darby, W.J. 1963. Evidence concerning the humanJ.. Clin. requirement Nutr. 12:117-29 for vitamin B12. Am.18. Bunge, M. M., Schilling, R. F. 1957.Intrinsic factor studies. VI. Competitionfor vitamin BI2 binding site offeredby analogues of the vitamin. Proc. Soc.Exp. Biol. Med. 96:587-9219. Burger, R. L., Allen, R. H. 1974. Characterizationof vitamin B12 binding proteinsisolated from human milk andsaliva by alfanity chromatography. ZBiol. Chem. 249:7220-2720. Burger, R. L., Mehlman, C. S., Allen,R. H. 1975. Human plasma R-type vitaminB~2 binding proteins. I. Isolationand characterization of transeobalaminI, transcobalamin III and the normalgranulocyte vitamin BI2 binding protein.J. Biol. Chem. 250:7700-621. Burger, R. L., Schneider, R. J., Mehlman,C. S., Allen, R. H. 1975. Humanplasma R-type vitamin B~ binding proteins.II. The role of TC I, TC III andnormal granulocyte vitamin B~-bindingprotein in plasma transport of vitaminB~. J. Biol. Chem. 250:7707-1322. Burgge, W. R., Goff, J. S., Allen, N. C.,Podell, E. R., Allen, R. H. 1980. Developmentof dual label Schilling test forpancreatic exocrine function based ondifferential absorption of eobalaminbound to intrinsic factor and R protein.Gastroenterology 78:937-4923. Burland, W. L., Mills, J. G., Sharpe, P.C., Horton, M. A., Mollin, D. L. 1977.The effect of eimetidine on intrinsicfactor secretion. In Cimetidine. Proc.Second Int. Syrup. Histamine H2 ReceptorAntagonist. Amsterdam: ExcerptaMed. p. 177-83.24. Burman, J. F., Molin, D. L., Sladden,R. A., Sourial, M., Greany, M. 1977.Inherited deficiency of transcobalaminII causing megaloblastic anemia. Brit. J.Hematol. 35:676-7725. Carmel, R., Herbert, V. 1969. Deftcieneyof vitamin Bin2 binding alphaglobulin in two brothers. Blood 33:1-1226. Carmel, R., Herbert, V. 1972. VitaminBt~ binding proteins of leukocytes as apossible major source of the third vitaminB~2-binding protein of serum. Blood40:542-4927. Castle, W. B., Townsend, W. C. 1929.Observation on the etiologic relationshipo.f achylia gastdca to perniciousanaerma. II. The effect of the administrationto patients with pernicious anaemiaof beef muscle after incubationwith Med. normal Sc~ 178:764-77 human gastric juice. An~ J.28. Chanarin, I. 1969. The MegaloblasticAnemias. Oxford: Blackwell29. Chanarin, I., Muir, M., Hughes, A.,
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Absorption and Transport of Cobalamin (Vitamin B12)

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