The involvement of dipeptidyl peptidase IV in brush-border degradation of GRF(1-29)NH2 by intestinal mucosal cells.
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.
Bai
J P
JP
College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Chang
L L
LL
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000187:drug effects; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D017337:Sermorelin / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D017337:Sermorelin; D018819:Dipeptidyl Peptidase 4