Transport and Metabolism of Radiolabeled Choline in Hepatocellular Carcinoma

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• 作者：Yu Kuang ; Nicolas Salem ; David J. Corn ; Bernadette Erokwu ; Haibin Tian ; Fangjing Wang ; Zhenghong Lee
• 刊名：Molecular Pharmaceutics
• 出版年：2010
• 出版时间：December 6, 2010
• 年：2010
• 卷：7
• 期：6
• 页码：2077-2092
• 全文大小：530K
• 年卷期：v.7,no.6(December 6, 2010)
• ISSN：1543-8392

文摘

Altered choline (Cho) metabolism in cancerous cells can be used as a basis for molecular imaging with PET using radiolabeled Cho. In this study, the metabolism of tracer Cho was investigated in a woodchuck hepatocellular carcinoma (HCC) cell line (WCH17) and in freshly derived rat hepatocytes. The transporter responsible for [¹¹C]-Cho uptake in HCC was also characterized in WCH17 cells. The study helped to define the specific mechanisms responsible for radio-Cho uptake seen on the PET images of primary liver cancer such as HCC. Cells were pulsed with [¹⁴C]-Cho for 5 min and chased for varying durations in cold media to simulate the rapid circulation and clearance of [¹¹C]-Cho. Radioactive metabolites were extracted and analyzed by radio-HPLC and radio-TLC. The Cho transporter (ChoT) was characterized in WCH17 cells. WCH17 cells showed higher ¹⁴C uptake than rat primary hepatocytes. [¹⁴C]-Phosphocholine (PC) was the major metabolite in WCH17. In contrast, the intracellular Cho in primary hepatocytes was found to be oxidized to betaine (partially released into media) and, to a lesser degree, phosphorylated to PC. [¹⁴C]-Cho uptake by WCH17 cells was found to have both facilitative transport and nonfacilitative diffusion components. The facilitative transport was characterized by Na⁺ dependence and low affinity (K_m = 28.59 ± 6.75 μM) with partial energy dependence. In contrast, ChoT in primary hepatocytes is Na⁺ independent and low affinity. Our data suggest that transport and phosphorylation of Cho are responsible for the tracer accumulation during [¹¹C]-Cho PET imaging of HCC. WCH17 cells incorporate [¹⁴C]-Cho preferentially into PC. Conversion of [¹⁴C]-PC into phosphatidylcholine occurred slowly in vitro. Basal oxidation and phosphorylation activities in surrounding hepatic tissue contribute to the background seen in [¹¹C]-Cho PET images.

Keywords:

Hepatocellular carcinoma; radiolabeled choline; positron emission tomography; choline transporter; choline metabolism; choline kinase; lipid synthesis; phosphocholine; betaine