PT  - JOURNAL ARTICLE
AU  - Michele Visentin
AU  - Angelo Torozi
AU  - Zhibo Gai
AU  - Stephanie Hausler
AU  - Chao Li
AU  - Christian Hiller
AU  - Peter H Schraml
AU  - Holger Moch
AU  - Gerd A Kullak-Ublick
TI  - Fluorocholine transport mediated by the organic cation transporter 2 (OCT2,SLC22A2): implication for imaging of kidney tumors
AID  - 10.1124/dmd.118.081091
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.081091
4099  - http://dmd.aspetjournals.org/content/early/2018/05/24/dmd.118.081091.short
4100  - http://dmd.aspetjournals.org/content/early/2018/05/24/dmd.118.081091.full
AB  - [18F]fluorocholine is the fluorinated analogue of [11C]choline and is used in positron emission tomography (PET) to monitor tumor metabolic activity. While important to optimize its use and expand the clinical indications, the molecular determinants of fluorocholine cellular uptake are poorly characterized. Here, we described the influx kinetics of fluorocholine mediated by the organic cation transporter 2 (OCT2, SLC22A2) and compared with that of choline. Then, we characterized the expression pattern of OCT2 in renal cell carcinoma (RCC). In HEK293 cells stably transfected with OCT2 fluorocholine influx kinetics was biphasic suggesting two independent binding sites: a high-affinity (Km = 14±8 μ;M, Vmax=1.3±0.5 nmol mg-1 min-1) and a low affinity component (Km = 1.8 ± 0.3 mM, Vmax=104±4.5 nmol mg-1 min-1). Notably, choline was found to be transported with sigmoidal kinetics typical of homotropic positive cooperativity (h=1.2, 95% CI 1.1-1.3). OCT2 mRNA expression level was found significantly decreased in primary but not in metastatic RCC. Tissue microarray immunostaining of 216 RCC biopsies confirmed that protein expression was consistent with the mRNA data. The kinetic properties described here suggest that OCT2 is likely to play a dominant role in [18F]fluorocholine uptake in vivo. OCT2 altered expression in primary and metastatic cancer cells, as compared with the surrounding tissues, could be exploited in RCC imaging, especially to increase the detection sensitivity for small metastatic lesions, a major clinical challenge during the initial staging of RCC.