title: Novel cationic and neutral glycocholic acid and polyamine conjugates able to inhibit transporters involved in hepatic and intestinal bile acid uptake.
abstract: To obtain novel drugs able to inhibit transporters involved in bile acid uptake, three compounds were synthesized by conjugating N-(3-aminopropyl)-1,3-propanediamine (PA) with one (BAPA-3), two (BAPA-6), or three (BAPA-8) moieties of glycocholic acid (GC) through their carboxylic group. The expected net charge in aqueous solutions was 2+ (BAPA-3), 1+ (BAPA-6), and 0 (BAPA-8). They were purified by liquid chromatography and their purity checked by HPLC before being chemically characterized by elemental analysis, NMR, and FAB-MS. Using brush-border membranes isolated from rat ileum; their ability to inhibit [(14)C]-GC transport (BAPA-3>BAPA-6>BAPA-8) was suggested. This was further investigated 48h after injecting Xenopus laevis oocytes with the mRNA of rat sodium/taurocholate (TC)-cotransporting polypeptide (Ntcp), rat apical sodium-dependent bile salt transporter (Asbt), or the human isoforms OATP-C/1B1 and OATP8/1B3 of organic anion-transporting polypeptides, when maximal functional expression was detected. BAPA-8, BAPA-6, and BAPA-3 induced no inhibition of OATP8/1B3-mediated [(3)H]-TC uptake, but dramatically reduced [(3)H]-TC uptake by OATP-C/1B1. In the cases of Ntcp- and Asbt-mediated [(3)H]-TC uptake, these were sodium-dependent and were inhibited by BAPA-6>BAPA-8>BAPA-3 and BAPA-8>BAPA-6>BAPA-3, respectively. In conclusion, our results suggest that these compounds are potentially interesting research tools for the selective modulation of liver and intestinal uptake of bile acids and other cholephilic compounds. Moreover, they may be of pharmacological usefulness to prevent the acute toxicity of compounds reaching liver cells through specific transporters or to enhance both fecal elimination of bile acids and hence cholesterol consumption for the 'de novo' synthesis of bile acids.
authors.affiliation: Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, CIBERHD, 37007 Salamanca, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicens
authors.forename: Manuel
authors.initials: M
authors.lastname: Medarde
authors.forename: Rocio I R
authors.initials: RI
authors.lastname: Macias
authors.forename: Monica G
authors.initials: MG
authors.lastname: Larena
authors.forename: Antonio
authors.initials: A
authors.lastname: Villafaina
authors.forename: Maria A
authors.initials: MA
authors.lastname: Serrano
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006000:Glycocholic Acid / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013656:Taurocholic Acid / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D011073:Polyamines; D012333:RNA, Messenger; D013656:Taurocholic Acid; D006000:Glycocholic Acid