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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Molecular Determinants in the Transport of a Bile Acid-Derived Diagnostic Agent in Tumoral and Nontumoral Cell Lines of Human Liver

Centro Studi Fegato, AREA Science Park and Department of Biochemistry, Biophysics, and Chemistry of Macromolecules, University of Trieste, Trieste, Italy (A.L., C.F., C.T., L.P.); Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského, Hradec Králové, Czech Republic (A.L., F.S.); and Bracco Imaging S.p.A., Milano, Italy (V.L., M.V., P.L.A.)

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a valuable technique for the diagnosis of liver diseases. As gadocoletic acid trisodium salt (B22956 [GenBank] /1), a new contrast agent showing high biliary excretion, may be potentially advantageous in hepatobiliary imaging, the aim of the study was to investigate the molecular mechanisms of hepatic transport of the B22956 [GenBank] ion in a cellular model of hepatic tumor. B22956 [GenBank] ion uptake was measured in tumoral (HepG2) and nontumoral (Chang liver) hepatic cell lines. Absolute quantitative real-time reverse transcriptase (RT)-polymerase chain reaction (PCR) analyses, using cloned PCR products as standards, were performed on total RNA of both cell lines and normal liver to evaluate the transcription of 12 transport genes: SLCO1A2, SLCO2B1, SLCO1B1, SLCO3A1, SLCO4A1, SLCO1B3, SLC22A7, SLC22A8, SLC22A1, SLC10A1, SLC15A1, and SLC15A2. B22956 [GenBank] transport was more efficient in Chang liver than in HepG2 cells and was inhibited by cholecystokinin-8, a specific substrate of OATP1B3. Real-time RT-PCR analyses revealed different transcription profiles in the tumoral and nontumoral cell lines. Compared with normal liver, the expression of SLCO1B1, SLCO3A1, and SLCO1B3 was greatly repressed in HepG2 cells, whereas SLCO2B1, SLC22A7, and SLC22A8 expression was either maintained or increased. On the contrary, in Chang liver cells, SLC22A7 and SLC22A8 genes were undetectable, whereas the expression of SLCO3A1, SLCO4A1, and SLCO1B3 was similar to normal liver. Transport studies and gene expression analyses indicated that B22956 [GenBank] ion is a good substrate to the liver-specific OATP1B3, reported to be poorly expressed or absent in human liver tumors. Therefore, B22956 [GenBank] may be helpful in detecting hepatic neoplastic lesions by CE-MRI.

Address correspondence to: Dr. Lorella Pascolo, Centro Studi Fegato, Bldg. Q, AREA Science Park Basovizza, SS 14 Km 163.5, 34012 Trieste, Italy. E-mail: lorella.pascolo{at}csf.units.it