Abstract
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 μM, whereas the natural chlorogenic acid (up to 100 μM) 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, α-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.
Footnotes
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Send reprint requests to: Dr. Hans-Joerg Burger, Aventis Pharma Deutschland GmbH, DG Metabolic Diseases, Bldg. H825, 65926 Frankfurt, Germany. E-mail: hans-joerg.burger{at}aventis.com
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↵1 Present address: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical Development-Drug Safety, Bldg. 69/155, 4070 Basel, Switzerland.
- Abbreviations:
- CHL
- chlorogenic acid
- Gl-6-P
- glucose 6-phosphate
- Gl-6-Pase
- glucose-6-phosphatase
- Ntcp
- bile salt cotransporting polypeptide
- Oatp
- organic anion transporting protein
- BSP
- sulfobromophthalein
- SLCT
- sulfolithocholyltaurine
- CHO
- Chinese hamster ovary
- Received June 5, 2000.
- Accepted September 18, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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