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Impact of organic cation transporters (OCT-SLC22A) on differential diagnosis of intrahepatic lesions


Visentin, M; van Rosmalen, B V; Hiller, C; Bieze, M; Hofstetter, L; Verheij, J; Kullak-Ublick, G A; Koepsell, H; Phoa, S S; Tamai, I; Bennink, R J; van Gulik, T M; Stieger, B (2017). Impact of organic cation transporters (OCT-SLC22A) on differential diagnosis of intrahepatic lesions. Drug Metabolism and Disposition, 45(2):166-173.

Abstract

Positron emission tomography (PET) using the cationic compound [18F]fluoromethylcholine (FCH) enhances the sensitivity for non-invasive classification of hepatic tumours 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 to 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 (FNH) compared to matched non-tumour tissues. In 3 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 supports the hypothesis that the varying expression levels of OCT1 and OCT3 in focal liver lesions determine FCH PET signal intensity.

Abstract

Positron emission tomography (PET) using the cationic compound [18F]fluoromethylcholine (FCH) enhances the sensitivity for non-invasive classification of hepatic tumours 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 to 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 (FNH) compared to matched non-tumour tissues. In 3 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 supports the hypothesis that the varying expression levels of OCT1 and OCT3 in focal liver lesions determine FCH PET signal intensity.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Date:2017
Deposited On:16 Dec 2016 10:48
Last Modified:14 Jan 2017 02:03
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0090-9556
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1124/dmd.116.072371
PubMed ID:27903597

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