Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

Abstract

Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success.

N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

“…The principal ATSs in cancer cells are ASCT2, LAT1 and ATB0,+, which have the appropriate characteristics for transporting NCAO because they have broad substrate specificity and participate in the transport of several drugs 62,64,[66][67][68] . Furthermore, a variety of drug transporters are expressed in HepG2 cells, including OATPs (organic anion transporting polypeptides) 69,70 and OCTs (organic cation transport) 71,72 . These transporters are highly expressed in HepG2 cells but hardly expressed in HeLa and MCF-7 cells 71,73 .…”

The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma

“…It has been recently shown that overall OCT1 (mRNA/protein) levels in tumor tissue detected using RT-QPCR, mRNA-microarray or immunoblotting may serve as a prognostic biomarker for the response to systemic treatment of HCC with this drug [13,14,17]. In the present study, we have taken a step forward by addressing the question on whether the presence of the transporter at its functional site in the plasma membrane, rather than its overall expression in tumor cells, is a better prognostic marker for the outcome of HCC patients treated with sorafenib.…”

“…The mechanism of action of sorafenib depends on its access to the intracellular site of action on transmembrane tyrosine kinase receptors, which may be affected by changes in the expression and activity of transporters accounting for its uptake. The organic cation transporter-1 (OCT1, gene symbol SLC22A1) has been suggested to play a major role in this process [13,14]. OCT1 functions as an electrogenic, sodium-and protonindependent bidirectional polyspecific transporter [15].…”

“…Human OCT1 is located at the basolateral membrane of hepatocytes, enterocytes, and renal proximal tubular cells, where it mediates the facilitated transport of a variety of structurally diverse organic cations, including endogenous and xenobiotic compounds, such as toxins and drugs [16]. Its role in sorafenib uptake has prompted us and other groups to investigate the usefulness of determining OCT1 expression in tumor tissue as a prognostic biomarker for the response to systemic treatment of HCC with this drug [13,14,17]. The identification of polymorphic genetic variants of human OCT1 that severely affect transport activity suggested that some of the inter-individual differences in response to cationic drugs may be caused by variable activity of this transporter among tumors [14].…”

“…Its role in sorafenib uptake has prompted us and other groups to investigate the usefulness of determining OCT1 expression in tumor tissue as a prognostic biomarker for the response to systemic treatment of HCC with this drug [13,14,17]. The identification of polymorphic genetic variants of human OCT1 that severely affect transport activity suggested that some of the inter-individual differences in response to cationic drugs may be caused by variable activity of this transporter among tumors [14]. Recently, two novel SLC22A1 variants R61S fs*10 and C88A fs*16 encoding truncated proteins unable to reach the plasma membrane of liver tumor cells together with an abundant proportion of aberrant alternative splicing have been described as common features in HCC [13].…”