Kontaxi M, Echkardt U, Hagenbuch B, Stieger B, Meier P J, Petzinger E
Institute of Pharmacology and Toxicology, Justus-Liebig-University, Giessen, Germany.
J Pharmacol Exp Ther. 1996 Dec;279(3):1507-13.
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.
赭曲霉毒素A（OTA）是一种由霉菌产生的霉菌毒素。作为谷物和动物饲料的主要致病性污染物，它主要导致人类和家畜患肾病。经口服摄取和肠道吸收后，大部分OTA被肝细胞摄取并排入胆汁。在本研究中，对分离的大鼠肝细胞中放射性标记的[3H]OTA的肝细胞摄取特性进行了表征；发现了一种可饱和的（K(m)=18.9微摩尔，Vmax=473皮摩尔/毫克/分钟）、温度（Aapp=30.4和76.6千焦耳/摩尔）和能量依赖性的霉菌毒素转运。这种OTA摄取受到各种胆汁酸、磺溴酞钠和凝血酶抑制剂CRC 220的抑制。由于所有抑制剂都是有机阴离子转运多肽（oatp）的底物，oatp是一种最近克隆的肝脏载体，因此在注射了oatp-cRNA的非洲爪蟾卵母细胞中进行了摄取实验。这些研究揭示了一种oatp特异性的OTA摄取（K(m)=16.6微摩尔）。相比之下，OTA不通过肝脏的Na+/牛磺胆酸盐共转运多肽转运。已知的oatp底物在注射了oatp-cRNA的卵母细胞中对OTA摄取有顺式抑制作用，这与从分离的肝细胞中得到的结果密切相关。这些结果确定OTA是oatp的一种新底物。它们进一步支持了oatp介导的转运的多特异性性质，并强调了这种载体对肝脏清除异生素的重要性。
