Positional requirements for anionic charge for ileal absorption of bile salt analogues

Previous structure-activity studies of the ileal bile salt cotransport system have suggested the idea that a coulombic interaction occurs between the negative charge of the bile salt and a cationic site on the carrier. Evidence included observations that modified bile salts with uncharged, cationic, or zwitterionic side chains were poorly transported. They did interact with this system as evidenced by their abilities to inhibit transport. Another prerequisite for coulombic interaction is positional (side-chain) specificity for the anionic grouping. [14C]chenodeoxycholyl-N-ethanolamide-O-sulfate and the 3 alpha-sulfate ester of chenodeoxycholyl-N-ethanolamide were tested for their in vivo absorption from the jejunums and ileums of anesthetized guinea pigs. Active ileal transport was estimated by subtracting jejunal absorption (passive) from ileal absorption (active and passive). Translocation of the anionic SO4(-) radical from the side chain to the 3 alpha position of the steroid decreased active ileal absorption by 95%, demonstrating a positional requirement for the anionic group for optimal transport.