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M Kontaxi, U Echkardt, B Hagenbuch, B Stieger, PJ Meier and E Petzinger
Institute of Pharmacology and Toxicology, Justus-Liebig-University, Giessen, Germany.
Ochratoxin A (OTA) is a mycotoxin produced by mold. It mainly causes nephropathies in humans and domestic animals as a major pathogenic contaminant of cereals and animal feed. Upon p.o. uptake and intestinal absorption, a large part of OTA is taken up by hepatocytes and eliminated into bile. In the present study, hepatocellular uptake of radiolabeled [3H]OTA in isolated rat hepatocytes was characterized; a saturable (K(m) = 18.9 microM, Vmax = 473 pmol/mg/min), temperature (Aapp = 30.4 and 76.6 kilo Joule/mol) and energy-dependent mycotoxin transport was found. This OTA uptake was inhibited by various bile acids, sulfobromophthalein and the thrombin inhibitor CRC 220. Because all inhibitors are substrates of the organic anion-transporting polypeptide (oatp), a recently cloned hepatic carrier, uptake experiments were performed in oatp-cRNA-injected Xenopus laevis oocytes. These studies revealed an oatp-specific OTA uptake (K(m) = 16.6 microM). In contrast, OTA was not transported by the hepatic Na+/taurocholate-cotransporting polypeptide. Known oatp substrates cis- inhibited OTA uptake in oatp-cRNA-injected oocytes in close correlation with the results derived from isolated hepatocytes. These results identify OTA as a new substrate for oatp. They further support the multispecific nature of oatp-mediated transport and stress the importance of this carrier for hepatic clearance of xenobiotics.
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