title: Impact of Organic Cation Transporters (OCT-SLC22A) on Differential Diagnosis of Intrahepatic Lesions.
abstract: Positron emission tomography (PET) using the cationic compound [18F]fluoromethylcholine (FCH) enhances the sensitivity for noninvasive classification of hepatic tumors due to peculiar patterns of accumulation. The underlying transporters are not known. We aim to identify the carriers mediating uptake of FCH in liver and to correlate their expression pattern with PET intrahepatic signal distribution to clarify the role of membrane transporters in FCH accumulation. FCH transport was characterized in cells overexpressing organic cation transporters (OCTs). OCT mRNA levels were determined in different types of hepatic lesions and correlated with FCH PET signal intensity. Additionally, OCT1 and OCT3 protein was analyzed in a subset of patients by Western blotting. HEK293 cells overexpressing OCT1, OCT2, or OCT3 showed higher intracellular levels of FCH in comparison with wild-type cells. mRNA levels of OCT1 paralleled protein levels and were significantly downregulated in hepatocellular carcinoma (HCC), hepatocellular adenoma (HCA), and, to a lesser extent, in focal nodular hyperplasia compared with matched nontumor tissues. In three patients with HCA, the FCH PET signal intensity was reduced relative to normal liver. This correlated with the simultaneous downregulation of OCT1 and OCT3 mRNA. In another patient with HCA, lesion and surrounding tissue did not show a difference in signal, coinciding with downregulation of OCT1 and upregulation of OCT3. Therefore, OCT1 is very likely a key transporter for the accumulation of FCH in the liver. The data support the hypothesis that the varying expression levels of OCT1 and OCT3 in focal liver lesions determine FCH PET signal intensity.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Michele
authors.initials: M
authors.lastname: Visentin
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Belle V
authors.initials: BV
authors.lastname: van Rosmalen
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Christian
authors.initials: C
authors.lastname: Hiller
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Matthanja
authors.initials: M
authors.lastname: Bieze
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Lia
authors.initials: L
authors.lastname: Hofstetter
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Saffire S K S
authors.initials: SS
authors.lastname: Phoa
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Roelof J
authors.initials: RJ
authors.lastname: Bennink
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.).
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland (M.V., C.H., L.H., G.A. K.-U., B.S.); Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (B.V.v.R., M.B., T.M.v.G.); Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (R.J.B.); Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (S.S.K.S.P.); Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.V.); Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Germany (H.K.); and Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan (I.T.) bruno.stieger@uzh.ch.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
mesh_terms: D018248:Adenoma, Liver Cell / Q000000981:diagnostic imaging* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging* / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003937:Diagnosis, Differential; D005260:Female; D005462:Fluorine Radioisotopes; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution; D000099254:Organic Cation Transporter 3
chemical_list: D002794:Choline; D005462:Fluorine Radioisotopes; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000099254:Organic Cation Transporter 3; C516370:fluoromethylcholine