title: Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo.
abstract: The peptide hormone gastrin binds two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated gastrins in vitro and in vivo. Bi3+ ions also bind to glycine-extended gastrin17 (Ggly), but inhibit Ggly-induced cell proliferation and migration in gastrointestinal cell lines in vitro. The aims of the present study were firstly, to establish the mechanism by which Bi3+ ions inhibit the binding of Fe3+ ions to Ggly, and secondly, to test the effect of Bi3+ ions on the activity of non-amidated gastrins in vivo. The interaction between Bi3+ ions, Fe3+ ions and Ggly was investigated by ultraviolet spectroscopy. The effect of Bi3+ ions on colorectal mucosal proliferation was measured in three animal models. In vitro in the presence of Bi3+ ions the affinity of Fe3+ ions for Ggly was substantially reduced; the data was better fitted by a mixed, rather than a competitive, inhibition model. In rats treated with Ggly alone proliferation in the rectal mucosa was increased by 318%, but was reduced to control values (p < 0.001) in animals receiving oral bismuth plus Ggly. Proliferation in the colonic mucosa of mice overexpressing Ggly or progastrin was significantly greater than in wild-type mice, but was no greater than control (p < 0.01) in animals receiving oral bismuth. Thus a reduction in the binding of Fe3+ ions to Ggly and progastrin in the presence of Bi3+ ions is a likely explanation for the ability of oral bismuth to block the biological activity of non-amidated gastrins in vivo.
authors.affiliation: The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Suzana
authors.initials: S
authors.lastname: Kovac
authors.forename: Su-Wen
authors.initials: SW
authors.lastname: Loh
authors.forename: Shamilah
authors.initials: S
authors.lastname: Lachal
authors.forename: Arthur
authors.initials: A
authors.lastname: Shulkes
authors.forename: Graham S
authors.initials: GS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism; D005260:Female; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005755:Gastrins; D019394:Ki-67 Antigen; D009942:Organometallic Compounds; D007501:Iron; C002791:bismuth tripotassium dicitrate