Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver.
OBJECTIVE
Cholecystokinin (CCK) is a major gastrointestinal peptide hormone that is released postprandially from the small intestine and exerts marked effects on gallbladder and gastrointestinal motility. The smaller isoforms CCK-8 and CCK-4 are rapidly taken up into hepatocytes, metabolized, and excreted into bile. Our aim was to identify and characterize the hepatocellular CCK-8 uptake system.


METHODS
CCK-8 uptake was measured in Xenopus laevis oocytes expressing the organic anion-transporting polypeptides of rat liver (Oatp1, Oatp2, Oatp3, or Oatp4) and of human liver (OATP-A, OATP-B, OATP-C, or OATP8) and in primary cultured rat hepatocytes.


RESULTS
Rat Oatp4 and human OATP8 efficiently mediated CCK-8 uptake in oocytes, with Michaelis constant (Km) values of 14.9 +/- 2.9 micromol/L and 11.1 +/- 2.9 micromol/L, respectively. CCK-8 uptake by hepatocytes was also saturable, with a Km of 6.7 +/- 2.1 micromol/L. The Km value in rat hepatocytes is consistent with Oatp4-mediated transport.


CONCLUSIONS
CCK-8 is selectively transported by rat Oatp4 and human OATP8, both of which are exclusively expressed at the basolateral membrane of hepatocytes. These 2 transporters are the first and probably the predominant hepatic uptake systems for CCK-8 and may be critical for the rapid clearance of this hormone from the circulation.
Ismair
M G
MG
Division of Clinical Pharmacology/Toxicology, Department of Internal Medicine, University Hospital, Zurich, Switzerland.
Stieger
B
B
Cattori
V
V
Hagenbuch
B
B
Fried
M
M
Meier
P J
PJ
Kullak-Ublick
G A
GA
D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014982:Xenopus laevis
D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D012844:Sincalide