Fluorescent 4-Nitrobenzo-2-oxa-1,3-diazole-Coupled Bile Acids as Probe Substrates of Hepatic and Intestinal Bile Acid Transporters of the Solute Carrier Families SLC10 and SLCO

J Med Chem. 2025 Jun 12;68(11):11724-11745. doi: 10.1021/acs.jmedchem.5c00589. Epub 2025 May 17.

Abstract

Several bile acid (BA) transporters are involved in the enterohepatic BA circulation between the liver and gut, including the hepatic Na+/taurocholate cotransporting polypeptide (NTCP) and the intestinal apical sodium-dependent BA transporter (ASBT). Fluorescent BA derivatives are helpful to measure and visualize BA transport in vitro and in vivo. We used 4-nitrobenzo-2-oxa-1,3-diazole (NBD) as the labeling fluorophore and synthesized a series of 3-NBD-coupled BA. While 3α-NBD-taurocholic acid, 3β-NBD-taurocholic acid, 3α-NBD-glycocholic acid, and 3β-NBD-glycocholic acid showed significant transport rates for human NTCP, mouse mNtcp, and mouse mAsbt, human ASBT only showed reliable transport activity for 3α-NBD-glycocholic acid. In general, NBD coupling to the 3α-position proved superior to the 3β-position, and the NBD-BA with glycine conjugation exhibited the highest overall transport rates. None of the synthesized NBD-BA was transported by the organic anion transporting polypeptides OATP1B1 and OATP1B3. Overall, 3α-NBD-glycocholic acid is most appropriate for fluorescence-based transport assays to evaluate NTCP and ASBT inhibitors.

MeSH terms

  • 4-Chloro-7-nitrobenzofurazan / analogs & derivatives
  • Animals
  • Bile Acids and Salts* / chemical synthesis
  • Bile Acids and Salts* / chemistry
  • Bile Acids and Salts* / metabolism
  • Fluorescent Dyes* / chemical synthesis
  • Fluorescent Dyes* / chemistry
  • Fluorescent Dyes* / metabolism
  • HEK293 Cells
  • Humans
  • Intestinal Mucosa / metabolism
  • Liver* / metabolism
  • Mice
  • Organic Anion Transporters* / metabolism
  • Organic Anion Transporters, Sodium-Dependent* / metabolism
  • Oxadiazoles* / chemistry
  • Oxadiazoles* / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Symporters* / metabolism

Substances

  • 4-Chloro-7-nitrobenzofurazan
  • Bile Acids and Salts
  • Fluorescent Dyes
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Dependent
  • Oxadiazoles
  • sodium-bile acid cotransporter
  • Symporters
  • Peptides