Cobalamin malabsorption due to nondegradation of R proteins in the human intestine. Inhibited cobalamin absorption in exocrine pancreatic dysfunction.

Abstract

A B S T R A C T In vivo studies demonstrate that the pancreatic enzymes and the ionic environment in the upper gastrointestinal tract are essential determining factors for transport and absorption of cobalamin in man.Jejunal fluid was aspirated from healthy human volunteers after administration of cyano[57Co]cobalamin preparations. Immunochemical analysis of the aspirates demonstrated that all isotopic vitamin was transferred to a protein that is identical to the gastric intrinsic factor in terms of molecular mass (57,500), ionic nature (mean pI, 5.09), and reactivity with antiintrinsic factor sera. However, in the aspirates from patients with exocrine pancreatic dysfunction the vitamin was found to be coupled >60% to a protein identical to R proteins in terms of molecular mass (125,000), ionic nature (mean pI, 3.51), and reactivity with anti-R protein and anti-intrinsic factor sera. The preferential transfer of cobalamin to R proteins in the patients and to intrinsic factor in healthy subjects was associated, respectively, with low and normal levels ofpancreatic enzymes in the intestine and these in turn were paralleled respectively by impaired and normal ileal absorption of cobalamin. These findings confirm the suggestion that the formation of unabsorbable cobalamin complexes may be the reason of impaired vitamin absorption in exocrine pancreatic insufficiency.This paper was presented in part at the 3rd European Symposium on Vitamin B12 and Intrinsic Factor, March 1979, Zurich, Switzerland.Dr. Marcoullis is a visiting professor of medicine under the auspices of Institut National de la Sante et de la Recherch6 Medicale at the University of Nancy. The permanent address for Dr. Marcoullis and Ms. Jimenez is Department of Medicine, Veterans Administration Hospital, Brooklyn, N. Y. Received for publication 2 November 1979 and in revised form 19 May 1980. 430 Observations made with other selected patients demonstrate: (a) that decreased enzyme activity and nondegradation of R proteins may also be due to nonactivation ofpancreatic zymogens in an acidic pH ofthe intestinal juice and; (b) that in the absence of an acidic environment in gastric juice the vitamin transported to the jejunum couples to intrinsic factor when pancreatic function is normal, and to intrinsic factor and R protein in exocrine pancreatic insufficiency. The observations made with these selected patients may explain why not all patients with exocrine pancreatic insufficiency develop impaired cobalamin absorption, and also why the malabsorption is corrected by the administration of bicarbonate in certain patients. INTRODUCTIONA common feature of the untreated exocrine pancreatic insufficiency (EPI)l is the impaired ileal absorption of cobalamin (Cbl; vitamin B,2) (1-8). The mechanism(s) underlying the pathophysiology of this phenomenon have not been worked out (8-12). The two principal prerequisites for normal Cbl absorption i.e., the complexing of dietary Cbl to the gastric intrinsic factor (IF) (gastric phase of Cbl transport), as well as th...

Crystal structure of human intrinsic factor: Cobalamin complex at 2.6-Å resolution

“…In humans, the genes for IF and HC are located in chromosome 22 (7,8), whereas the gene for TC is located in chromosome 11 (9). Human IF contains 399-aa residues plus Ϸ15% carbohydrate, giving it a molecular mass of Ϸ60 kDa, as observed by gel filtration (10)(11)(12)(13). All three proteins promote Cbl entry through endocytosis involving distinct cell surface receptors (5,(14)(15)(16)(17)(18)(19)(20).…”

Biliary Excretion of Cobalamin and Cobalamin Analogues in Man

“…la), and it resembled the isoelectrofocusing pattern of salivary or gastric R binder [17,20], The isoelectrofocusing profile of saturated biliary R binder of patients 1 and 2 showed 4 welldefined isoproteins with a mean isoelectric point of 3.61 ( fig. 2b).…”

Vitamin B12 Transporters

“…After passing through the stomach, Hc undergoes degradation by pancreatic proteases (Allen et al, 1978;Marcoullis et al, 1980). In the newborn animal (and in the mouse and rat prior to weaning) synthesis and secretion of pancreatic enzymes is quite limited, and much of the Hc derived from milk, salivary, gastric, or pancreatic sources survives intact in the intestinal lumen.…”