Liver, Pancreas, and Biliary TractDrug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver☆,☆☆
Section snippets
Cell culture
Sf9 cells were obtained from Pharmingen (San Diego, CA) and kept at 27°C under standard conditions. Infections with baculoviruses encoding Bsep8 were performed with a multiplicity of infection (MOI) of 10 and 3 days of incubation before subcellular fractionation. Mrp2 recombinant baculovirus11 was generated with the Bac-to-Bac system (Life Technologies Inc., Gaithersburg, MD). Sf9 cells were infected with Mrp2-encoding baculovirus at MOI of 7.5 and incubated for 2 days before subcellular
Functional expression of Bsep in baculovirus-infected Sf9 cells
In mammalian (including human) liver, the canalicular secretion of anionic bile salts and nonbile salt organic anions is mediated by the 2 separate ABC transporters Bsep (BSEP) and Mrp2 (MRP2).17 These complementary transport functions were confirmed by the separate expression of rat liver Bsep and Mrp2 in baculovirus-infected Sf9 cells (Table 1). Although membrane vesicles from Sf9 cells infected with the wild-type baculovirus did not exhibit any ATP-dependent transport activities, infection
Discussion
Canalicular bile salt secretion is the major driving force of hepatic bile formation. In our previous study, the so-called sister of P-glycoprotein32 was identified as a canalicular ATP-dependent Bsep in rat liver.8 In parallel, the coding region of the human BSEP gene has been elucidated, and several mutations predicted to disrupt BSEP gene function have been identified in patients with type 2 of PFIC (PFIC-2).2 The phenotype of PFIC-2 is entirely consistent with an isolated defect in
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Supported in part by grants 3100-045536.95 and 3200-052190.97 from the Swiss National Science Foundation and a SCORE-A clinical research development award of the Swiss National Science Foundation (to K.F.).
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Address requests for reprints to: Peter J. Meier-Abt, Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. e-mail: [email protected]; fax: (41) 1-255-4411.