Organic Anion Uptake by Hepatocytes

Abstract

Many of the compounds taken up by the liver are organic anions that circulate tightly bound to protein carriers such as albumin. The fenestrated sinusoidal endothelium of the liver permits these compounds to have access to hepatocytes. Studies to characterize hepatic uptake of organic anions through kinetic analyses, suggested that it was carrier-mediated. Attempts to identify specific transporters by biochemical approaches were largely unsuccessful and were replaced by studies that utilized expression cloning. These studies led to identification of the organic anion transport proteins (oatps), a family of 12 transmembrane domain glycoproteins that have broad and often overlapping substrate specificities. The oatps mediate Na+-independent organic anion uptake. Other studies identified a seven transmembrane domain glycoprotein, Na+/taurocholate transporting protein (ntcp) as mediating Na+-dependent uptake of bile acids as well as other organic anions. Although mutations or deficiencies of specific members of the oatp family have been associated with transport abnormalities, there have been no such reports for ntcp, and its physiologic role remains to be determined, although expression of ntcp in vitro recapitulates the characteristics of Na+-dependent bile acid transport that is seen in vivo. Both ntcp and oatps traffic between the cell surface and intracellular vesicular pools. These vesicles move through the cell on microtubules, using the microtubule based motors dynein and kinesins. Factors that regulate this motility are under study and may provide a unique mechanism that can alter the plasma membrane content of these transporters and consequently their accessibility to circulating ligands.

Rat Organic Anion Transport Protein 1A1 Interacts Directly With Organic Anion Transport Protein 1A4 Facilitating Its Maturation and Trafficking to the Hepatocyte Plasma Membrane

“…P revious studies showed that the hepatocyte efficiently eliminates organic anions from the circulation with single-pass extraction as high as ≥50%. (1) Pharmacokinetic studies were consistent with carrier mediation, (2,3) and subsequent functional cloning experiments identified a transport protein, initially named organic anion transporting polypeptide (OATP). (4,5) This 75-kDa glycoprotein has 12 transmembrane domains (6) and is sufficient to mediate ligand transport when transfected into various cell lines.…”

“…Pijun Wang, 1 Wen-Jun Wang, 1,2 Jo Choi-Nurvitadhi, 1,2 Yaniuska Lescaille, 1,3 John W. Murray, 1,2 and Allan W. Wolkoff [1][2][3] Organic anion transport proteins (OATPs) on the basolateral surface of hepatocytes mediate uptake of a number of drugs and endogenous compounds. Previous studies showed that rat OATP1A1 (rOATP1A1) has a postsynaptic density protein, drosophila disc large tumor suppressor, zonula occludens-1 protein (PDZ) consensus binding motif at its C-terminus and binds to PDZ domain containing 1 (PDZK1), which is required for its cell-surface localization.…”

“…(7,8) Since its initial discovery, over 20 additional members of the OATP family have been described. (1) All are 12 transmembrane domain glycoproteins with overlapping substrate specificities and tissue distributions. The original OATP is now known as rat OATP1A1 (rOATP1A1) and is a member of the solute carrier organic anion transporter (SLCO) family (9) with the gene name Slco1a1.…”

“…This 75‐kDa glycoprotein has 12 transmembrane domains and is sufficient to mediate ligand transport when transfected into various cell lines . Since its initial discovery, over 20 additional members of the OATP family have been described . All are 12 transmembrane domain glycoproteins with overlapping substrate specificities and tissue distributions.…”

“…Although many members of the OATP family possess PDZ consensus binding motifs at their C‐termini, an almost equal number do not . In particular, rat OATP1A4 does not have a PDZ binding motif whereas its very close mouse homolog does (KTKL).…”