The involvement of dipeptidyl peptidase IV in brush-border degradation of GRF(1-29)NH2 by intestinal mucosal cells.

The Journal of pharmacy and pharmacology1995PMID: 8583376

Plain Language Summary

Researchers investigated how sermorelin (GRF 1-29) is broken down in intestinal cells and found that the same enzyme responsible for its degradation in blood -- dipeptidyl peptidase IV -- is also the main enzyme degrading it in the gut lining. A modified sermorelin analog designed to resist this enzyme in blood was also much more stable in intestinal tissue, suggesting that protecting peptides from plasma enzymes simultaneously improves their oral bioavailability.

Abstract

GRF(1-29)NH2 is degraded mainly by dipeptidyl peptidase IV (DPP IV) in plasma, resulting in inactivated GRF(3-29)NH2. To understand whether improving stability of GRF(1-29)NH2 in the plasma will result in enhanced stability in intestinal mucosal cells, stability of GRF(1-29)NH2 and [desNH2Tyr1,D-Ala2,Ala15]-GRF(1-29)NH2 in rat intestine brush-border membrane and homogenate was examined. [desNH2Tyr1,D-Ala2,Ala15]-GRF(1-29)NH2, resistant to plasma DPP IV, was much more stable than GRF(1-29)NH2 in enterocytes. Gradient HPLC analysis, mass balance analysis and studies of inhibitor effects revealed that GRF(3-29)NH2 was the major metabolite of GRF(1-29)NH2 due to the action of DPP IV during incubation with brush-border membranes. It is concluded that the design of peptide analogues to resist plasma enzymes dramatically increases stability in intestinal epithelium.

Authors

Bai, J P; Chang, L L