Metabolism of recombinant progastrin in sheep.
Precursor forms of peptide hormones may be biologically active with effects distinct from the mature end product. Nonamidated progastrin-derived peptides stimulate growth of colonic epithelium and are elevated in the circulation of patients with colorectal carcinomas, whereas the amidated end product is the major regulator of gastric acidity. Using region-specific radioimmunoassays, we here compared the in vitro and in vivo metabolism of recombinant human progastrin-(6-80) and two other nonamidated gastrins, gastrin-17-Gly and Tyr(70)-progastrin-(71-80). Although progastrin-(6-80) was very stable in vitro, both progastrin-(6-80) and gastrin-17-Gly were degraded in vivo. The in vivo data were best fitted by a double-exponential decay curve, and the half-lives for progastrin-(6-80) (t1/2alpha = 5.1 +/- 1.1, t(1/2)beta = 42 +/- 11 min) were significantly (P < 0.05) longer than for gastrin-17-Gly (t(1/2)alpha = 2.2 +/- 0.6, t(1/2)beta = 13 +/- 1 min). Tyr(70)-progastrin-(71-80) was degraded more rapidly. Comparison with amidated gastrins suggests that peptide length, rather than sequence, is the critical determinant of clearance. Progastrin has the clearance characteristics to be considered a circulating hormone.
Paterson
Adrienne C
AC
Department of Surgery, University of Melbourne, Austin, and Repatriation Medical Centre, Melbourne, Victoria 3084, Australia.
Baldwin
Graham S
GS
Shulkes
Arthur
A
D000818:Animals; D005755:Gastrins / Q000097:blood* / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000097:blood; D011498:Protein Precursors / Q000097:blood* / Q000737:chemistry; D011994:Recombinant Proteins / Q000097:blood; D012756:Sheep
D005755:Gastrins; D010446:Peptide Fragments; D011498:Protein Precursors; D011994:Recombinant Proteins; C013706:big gastrin