Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor: <i>IN VIVO EVIDENCE THAT A FAILURE TO PARTIALLY DEGRADE R PROTEIN IS RESPONSIBLE FOR COBALAMIN MALABSORPTION IN PANCREATIC INSUFFICIENCY</i>

Robert H. Allen; Bellur Seetharam; Nancy C. Allen; Elaine R. Podell; David H. Alpers

doi:10.1172/JCI109083

Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor: IN VIVO EVIDENCE THAT A FAILURE TO PARTIALLY DEGRADE R PROTEIN IS RESPONSIBLE FOR COBALAMIN MALABSORPTION IN PANCREATIC INSUFFICIENCY

Robert H. Allen, Bellur Seetharam, Nancy C. Allen, Elaine R. Podell, and David H. Alpers

Published June 1, 1978 - More info

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Abstract

In vitro studies indicate that [⁵⁷Co]cobalamin (Cbl) is preferentially bound to salivary R protein as opposed to intrinsic factor (IF) and that [⁵⁷Co]Cbl bound to R protein is not transferred to IF at either pH 2 or pH 8. Incubation of R protein-[⁵⁷Co]Cbl with pancreatic proteases causes a partial degradation of the R protein moiety and a rapid transfer of [⁵⁷Co]Cbl to IF. We have postulated that the etiology of Cbl malabsorption in pancreatic insufficiency is an inability to partially degrade R protein because of a lack of pancreatic proteases. We have tested this hypothesis by determining the ability of a nonradioactive Cbl analogue, bound with high affinity by R protein but not by IF, to correct the malabsorption of [⁵⁷Co]Cbl in patients with pancreatic insufficiency.

R protein bound the Cbl analogue known as cobinamide with affinities that were the same and only 14-fold lower than those for Cbl at pH 8 and pH 2, respectively. Cobinamide was bound by IF with affinities that were 600,000- and 10,000-fold lower than those for Cbl at pH 8 and 2, respectively. The addition of 125 pmol of nonradioactive cobinamide to 0.5 pmol of [⁵⁷Co]Cbl before being added to 1 pmol of R protein and 1 pmol of IF, markedly inhibited the ability of R protein to compete with IF for binding the [⁵⁷Co]Cbl. Similar results were obtained with freshly aspirated gastric juice. This change was essentially indistinguishable from that observed previously when R protein or R protein-[⁵⁷Co]Cbl was incubated in vitro with trypsin. The oral administration of 100 nmol of nonradioactive cobinamide in Schilling tests was equivalent to trypsin in its ability to completely correct the malabsorption of 0.4 nmol of [⁵⁷Co]Cbl in three patients with pancreatic insufficiency.

The fact that both trypsin and nonradioactive cobinamide inhibit the ability of R protein to compete with IF for [⁵⁷Co]Cbl binding in vitro, and correct the mal-absorption of [⁵⁷Co]Cbl in patients with pancreatic insufficiency in vivo, supports our hypothesis that the primary defect in Cbl absorption in this disease is an inability to partially degrade R protein because of a lack of pancreatic proteases.

Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor: IN VIVO EVIDENCE THAT A FAILURE TO PARTIALLY DEGRADE R PROTEIN IS RESPONSIBLE FOR COBALAMIN MALABSORPTION IN PANCREATIC INSUFFICIENCY

Robert H. Allen, Bellur Seetharam, Nancy C. Allen, Elaine R. Podell, and David H. Alpers

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Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor: IN VIVO EVIDENCE THAT A FAILURE TO PARTIALLY DEGRADE R PROTEIN IS RESPONSIBLE FOR COBALAMIN MALABSORPTION IN PANCREATIC INSUFFICIENCY

Robert H. Allen, Bellur Seetharam, Nancy C. Allen, Elaine R. Podell, and David H. Alpers

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