Transport and Metabolism of Radiolabeled Choline in Hepatocellular Carcinoma

Abstract

Objectives-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 [ 11 C]-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.Methods-Cells were pulsed with [ 14 C]-Cho for 5 min and chased for varying durations in cold media to simulate the rapid circulation and clearance of [ 11 C]-Cho. Radioactive metabolites were extracted and analyzed by radio-HPLC and radio-TLC. The Cho transporter (ChoT) was characterized in WCH17 cells.Results-WCH17 cells showed higher 14 C uptake than rat primary hepatocytes. [ 14 C]-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 less degree, phosphorylated to PC. [ 14 C]-Cho uptake by WCH17 cells was found to have both facilitative transport and non-facilitative 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. Conclusions-Our

Imaging Lipid Synthesis in Hepatocellular Carcinoma with [Methyl-11C]Choline: Correlation with In Vivo Metabolic Studies

“…Several in vitro studies on the metabolism of radiolabeled choline in tumor cells have suggested that phosphocholine produced from the phosphorylation of 14 C-choline is the main contributor of the observed tracer accumulation (20)(21)(22)(23). These studies closely agree with the results from our earlier in vitro study (24). In addition, a previous study on the in vivo distribution of fluorocholine in 9L-gliomabearing Fisher rats showed that up to 99% of tumor uptake was in the water-soluble fraction after 5 min after injection and that uptake became stable by 20 min after injection (20).…”

Evaluation of Deuterated 18F- and 11C-Labeled Choline Analogs for Cancer Detection by Positron Emission Tomography

“…Further incorporation of phosphocholine to membrane phosphatidylcholine is negligible within this time window (7,8,14,15). Chromatographic analysis also indicates that further betaine metabolism or conversion to acetylcholine is negligible (16,17).…”

Functional imaging techniques in hepatocellular carcinoma

“…11 C and 18 F-F-Cho PET Increased concentrations of choline have been confirmed in surgical HCC specimens [26]. In the hepatitis viral infection-induced woodchuck model it has been shown that HCC is associated with increased transport and phosphorylation of 11 C-Cho and that the increased accumulation of radiolabelled choline reflects increased phosphatidylcholine synthesis [27,28]. A study in the same animal model has shown a small preferential uptake of 11 C-Cho compared to 18 F-fluoroethylcholine in terms of tumour-to-background contrast [29].…”