Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology

Abstract

Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1–3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.

G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic

“…4 d and Supplementary Table S1 ). Finally, due to the importance of glycosylation in neuroserpin polymerization in FENIB 23 , 25 , we exposed neuronal cultures to an alternative source of fully glycosylated neuroserpin by co-culturing the primary neurons with HEK-293 cells stably overexpressing and secreting either wild-type or G392E-mutant neuroserpin for 18 h. Again, no significant differences in density or area of synaptic puncta were observed (Fig. 4 d and Supplementary Table S1 ).…”

“…To address toxicity in post-mitotic neurons, we used primary, fully differentiated hippocampal neurons and treated them with recombinant G392E-mutant neuroserpin used at 20 nM, a concentration of the serpin shown before to be, in its wild-type form, well tolerated by primary hippocampal neurons and protective against oxidative stress 34 , or 100 nM. To address the possibility that glycosylation plays a role in the extracellular effects of neuroserpin, maybe through an increase in polymer formation as reported before 23 , 25 , we extended our analysis by co-culturing primary neurons with HEK-293 cells stably expressing wild-type or G392E-mutant neuroserpin. We used a density of HEK-293 cells that was well tolerated by neurons and similar to experiments where extracellular polymers were easily detectable.…”

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy

“…Multiple transporters have been reported for oxaliplatin, i.e., the organic cation transporter system (SLC22A), including OCT2 (SLC22A2) [13] and OCT3 (SLC22A3) [14], organic cation/carnitine transporters OCTNs (OCTN1/OCTN2) [15], and multidrug resistance protein 4 (MRP4) [16]. OCTs are a group of poly-specific transporters for subtracts typically of positively charged or zwitterions at physiological pH conditions, e.g., organic amines choline, neurotransmitters dopamine and serotonin, and vitamin B (thiamine) [17]. In one study, it was reported that long progression-free survival (PFS) in metastatic colon cancer treated with oxaliplatin is linked to high expression of OCT2 [18], implicating the role of this transporter in oxaliplatin treatment.…”

Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations

“…In this Special Issue, the readers will find integrative information on transporters for organic cations. Besides reviews on physiology, pharmacology, and toxicology of these transporters [ 1 , 2 , 3 ], which offer a concise overview of the field, the readers will find original research work focusing on specific transporter aspects.…”

“…Specifically, the review “Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology” by Samodelov et al [ 1 ] summarizes well the general aspects of physiology, pharmacology, and toxicology of transporter for organic cations. The other review “Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts” by Ali Selo et al [ 2 ] focuses on these aspects of transporters for organic cations in the lung, an important but often neglected field.…”