Visentin Michele, van Rosmalen Belle V, Hiller Christian, Bieze Matthanja, Hofstetter Lia, Verheij Joanne, Kullak-Ublick Gerd A, Koepsell Hermann, Phoa Saffire S K S, Tamai Ikumi, Bennink Roelof J, van Gulik Thomas M, Stieger Bruno
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.).
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.)
Drug Metab Dispos. 2017 Feb;45(2):166-173. doi: 10.1124/dmd.116.072371. Epub 2016 Nov 30.
Positron emission tomography (PET) using the cationic compound [F]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.
使用阳离子化合物[F]氟甲基胆碱（FCH）的正电子发射断层扫描（PET），因其独特的积聚模式，提高了肝肿瘤无创分类的敏感性。其潜在的转运体尚不清楚。我们旨在确定介导FCH在肝脏摄取的载体，并将其表达模式与PET肝内信号分布相关联，以阐明膜转运体在FCH积聚中的作用。在过表达有机阳离子转运体（OCTs）的细胞中对FCH转运进行了表征。测定了不同类型肝损伤中OCT的mRNA水平，并将其与FCH PET信号强度相关联。此外，通过蛋白质印迹法分析了一部分患者的OCT1和OCT3蛋白。与野生型细胞相比，过表达OCT1、OCT2或OCT3的HEK293细胞显示细胞内FCH水平更高。与匹配的非肿瘤组织相比，OCT1的mRNA水平与蛋白水平平行，在肝细胞癌（HCC）、肝细胞腺瘤（HCA）以及程度较轻的局灶性结节性增生中显著下调。在3例HCA患者中，FCH PET信号强度相对于正常肝脏降低。这与OCT1和OCT3 mRNA的同时下调相关。在另一例HCA患者中，病变组织和周围组织的信号无差异，这与OCT1下调和OCT3上调一致。因此，OCT1很可能是FCH在肝脏中积聚的关键转运体。这些数据支持以下假设：局灶性肝损伤中OCT1和OCT3表达水平的变化决定了FCH PET信号强度。
