Cobalamin Analogues in the Rabbit EVIDENCE FOR THE EXISTENCE OF MULTIPLE MECHANISMS THAT PREVENT THE ABSORPTION AND TISSUE DISSEMINATION OF NATURALLY OCCURRING COBALAMIN ANALOGUES

This work was presented in part at The Annual Meeting of the American Federation for Clinical Research, Atlantic City, N. J., May 1976. (1) The present address for Dr. Kolhouse and Dr. Allen is: Division of Hematology, University of Colorado Medical Center, Denver, Colo. 80220. Received for publication 11 May 1977 and in revisedform 3 August 1977. with native Cbl when it is present in plasma in unbound form. All of the Cbl analogues were bound by the granulocyte R-type Cbl-binding protein with high affinity and all ofthe R-type protein-[57Co]Cbl analogue complexes were cleared rapidly from plasma exclusively by hepatocytes as occurs with R-type protein-[58Co]Cbl. Some Cbl analogues were released back into the plasma and were disseminated among a variety of tissues via transcobalamin II as occurs with native Cbl. Other Cbl analogues were retained in the liver and eventually excreted in the feces and urine without accumulating in other tissues. These studies indicate that intrinsic factor and the ileum prevent certain Cbl analogues from entering the body and that the granulocyte R-type protein and hepatocytes prevent the dissemination of certain Cbl analogues that may gain entry such as during infections with Cbl analogue-producing bacteria. The fact that transcobalamin II binds and transports a large number of Cbl analogues indicates that these protective mechanisms can be circumvented and supports the feasibility of using Cbl analogues as antimetabolites in vivo.