Influence of albumin binding on the substrate transport mediated by human hepatocyte transporters OATP2 and OATP8.
BACKGROUND
Despite their strong binding to albumin while circulating in blood, many organic anions, such as bilirubin and fatty acids, are removed efficiently by the liver. The uptake transporters of human hepatocytes, OATP2 (symbol, SLC21A6) and OATP8 (SLC21A8), play important roles in the hepatic uptake of endogenous substances and drugs. The two transporters show different affinities for the organic anion sulfobromophthalein (BSP), which binds with high affinity to albumin in blood.


METHODS
In this study, we investigated whether a direct interaction of albumin with OATP2 or OATP8 occurs during the uptake of BSP. The uptake of BSP, at varying concentrations of human serum albumin (HSA), into transfected HEK293 cells expressing recombinant human OATP2 or OATP8 was measured. The influence of other organic anions on the uptake of albumin-bound BSP by OATP2 or OATP8 was also studied.


RESULTS
OATP8-mediated transport was affected more strongly by HSA than OATP2-mediated transport. Albumin affected both transporters in the manner of a noncompetitive inhibitor. Uptake studies using OATP2-transfected MDCKII cells indicated that a direct interaction between albumin and OATP2 is not necessary for uptake, a finding that was further confirmed by the effects of bilirubin and palmitate on the binding of BSP to albumin and on the uptake of BSP by OATP2 or OATP8.


CONCLUSIONS
Our results indicated that uptake of albumin-bound BSP occurs only from the pool of unbound ligand.
Cui
Yunhai
Y
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Walter
Bettina
B
D001663:Bilirubin / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1 / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D010168:Palmitates / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D012709:Serum Albumin / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein / Q000378:metabolism
D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D010168:Palmitates; C421209:SLCO1B3 protein, human; D012709:Serum Albumin; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein; D001663:Bilirubin