Hepatic uptake of synthetic chlorogenic acid derivatives by the organic anion transport proteins.
Chlorogenic acid derivatives were recently identified as novel, potent, and specific inhibitors of the hepatic glucose 6-phosphate translocase. Inhibition of the glucose 6-phosphate translocase leads to a decrease in hepatic glucose production, rendering chlorogenic acid derivatives as potential novel therapeutics in patients with type 2 diabetes. The present study examines the hepatic uptake mechanism of the radiolabeled chlorogenic acid derivative S 1743 into freshly isolated rat hepatocytes. Initial uptake rates were Na(+)-independent and followed saturation kinetics with no superimposition of facilitated diffusion. Inhibition studies demonstrated that other chlorogenic acid derivatives inhibited uptake of the radiolabeled compound S 1743 into rat hepatocytes in the range of 1.1 to 11 microM, whereas the natural chlorogenic acid (up to 100 microM) had no effect at all. In addition, inhibition of S 1743 uptake into rat hepatocytes was found in the presence of sulfobromophthalein, sulfolithocholyltaurine, estrone-3-sulfate, cholyltaurine, verapamil, bumetanide, probenecide, phenol red, digoxin, and ouabain (in decreasing order) but not with N-methylnicotinamide, alpha-ketoglutarate, p-aminohippurate, geneticin sulfate, and 5-sulfosalicylate. The observed inhibition pattern suggested that members of the family of the organic anion transporting polypeptides (Oatps) could be involved in hepatic uptake of chlorogenic acid derivatives. Indeed, S 1743 uptake could be demonstrated in Oatp1- and Oatp2-expressing Xenopus laevis oocytes as well as in Oatp1-expressing Chinese hamster ovary cells. A comparison of the inhibition pattern obtained in hepatocytes compared with that obtained in Oatp1-expressing Chinese hamster ovary cells suggests that facilitated uptake by Oatp1 is a major contributor in total hepatic uptake of chlorogenic acid derivatives.
Schwab
D
D
Aventis Pharma Deutschland GmbH, Frankfurt am Main, Germany.
Herling
A W
AW
Hemmerle
H
H
Schubert
G
G
Hagenbuch
B
B
Burger
H J
HJ
D000818:Animals; D027321:Anion Transport Proteins; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D006224:Cricetinae; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000378:metabolism*; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D002352:Carrier Proteins; C119524:S 1743; D013449:Sulfonamides; D002726:Chlorogenic Acid; D000226:Mitochondrial ADP, ATP Translocases