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Function of Both Sinusoidal and Canalicular Transporters Controls the Concentration of Organic Anions within Hepatocytes

Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire (C.P., J.B., C.M.P.); Division de Gastroentérologie et Hépatologie (A.H., A.V., J.L.F., R.Q.); and Département de Radiologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland (C.D.B.); and Klinische Pharmakologie und Toxicologie, UniversitätsSpital Zürich, Zurich, Switzerland (B.S.)

We hypothesized that the function of both sinusoidal and canalicular transporters importantly controls the concentrations of organic anions within normal hepatocytes. Consequently, we investigated how acute transport regulation of the sinusoidal organic anion transporting polypeptides (Oatps) and the canalicular multidrug resistance associated protein 2 (Mrp₂) determines the hepatic concentrations of the organic anion gadolinium benzyloxypropionictetraacetate (BOPTA) in rat livers. Livers were perfused with labeled BOPTA in different experimental settings that modify the function of Oatps and Mrp₂ through the protein kinase C (PKC) pathway. Intrahepatic concentrations were continuously measured with a gamma probe placed above rat livers. Labeled BOPTA was also measured in perfusate and bile. We showed that when the function of Oatps and Mrp₂ is modified in such a way that BOPTA entry and exit are similarly decreased, concentrations of organic anions within hepatocytes remain unaltered. When exit through Mrp₂ is abolished, hepatic concentrations are high if entry through Oatps is only slightly decreased (livers without Mrp₂ expression) or low if BOPTA uptake is more importantly decreased (livers perfused with a PKC activator). These results highlight that the function of both sinusoidal and canalicular transporters is important to determine the concentration of organic anions within hepatocytes.

Received for publication September 18, 2006.

Accepted for publication January 16, 2007.

Address correspondence to: Dr. Catherine M. Pastor, Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Rue Micheli-du-Crest, 24, 1205 Geneva, Switzerland. E-mail: catherine.pastor{at}hcuge.ch

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