Organic cation transporters

Abstract

Over the last 15 years, a number of transporters that translocate organic cations were characterized functionally and also identified on the molecular level. Organic cations include endogenous compounds such as monoamine neurotransmitters, choline, and coenzymes, but also numerous drugs and xenobiotics. Some of the cloned organic cation transporters accept one main substrate or structurally similar compounds (oligospecific transporters), while others translocate a variety of structurally diverse organic cations (polyspecific transporters). This review provides a survey of cloned organic cation transporters and tentative models that illustrate how different types of organic cation transporters, expressed at specific subcellular sites in hepatocytes and renal proximal tubular cells, are assembled into an integrated functional framework. We briefly describe oligospecific Na(+)- and Cl(-)-dependent monoamine neurotransmitter transporters ( SLC6-family), high-affinity choline transporters ( SLC5-family), and high-affinity thiamine transporters ( SLC19-family), as well as polyspecific transporters that translocate some organic cations next to their preferred, noncationic substrates. The polyspecific cation transporters of the SLC22 family including the subtypes OCT1-3 and OCTN1-2 are presented in detail, covering the current knowledge about distribution, substrate specificity, and recent data on their electrical properties and regulation. Moreover, we discuss artificial and spontaneous mutations of transporters of the SLC22 family that provide novel insight as to the function of specific protein domains. Finally, we discuss the clinical potential of the increasing knowledge about polymorphisms and mutations in polyspecific organic cation transporters.

Chronic Myeloid Leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 Activity

“…OCT-1 belongs to the solute carrier superfamily and is responsible for the distribution and elimination of organic cations in vivo. 16,17 Using our established intracellular uptake and retention (IUR) assay, 14 we have shown that the functional activity of OCT-1 (OCT-1 Activity) in mononuclear cells (MNC) derived from CML patients is significantly related to their molecular response to imatinib treatment. 18 In addition, other studies have observed a relationship between OCT-1 mRNA levels and achievement of cytogenetic responses to imatinib.…”

Transport of six tyrosine kinase inhibitors: active or passive?

“…To achieve this, Caco-2 cells were cultured as described above at 37 °C. After 36 hours, to allow proper attachment, cells were exposed to either 100 µM amantadine (hOCT1&2), 100 µM cimetidine (hOCT1&2&3) [37], 100 µM desipramine (hOCT1&2&3), 10 µM β-estradiol (hOCT1&3) or 10 µM verapamil (hOCT1&P-gp) [28,35,36] for 15 min. Then attached cells were exposed to 10 µM erlotinib, gefitinib, sorafenib, sunitinib, crizotinib or 1 µM dasatinib for 2 hours at 37 °C.…”

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

“…Table I), and the identification and characterization of interactions with the hOCT have been primarily accomplished using competitive binding, cellular uptake and trans -stimulation studies (cf. Zhang et al 1998; Koepsell et al 2003; Moaddel et al 2005a). …”

“…This family has been recently reviewed (Koepsell et al 2003) and is addressed in this special issue. These transporters interact with a broad range of substrates and inhibitors and, as in the case of Pgp, stereoselective interactions have been reported.…”