Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications

Abstract

The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 (SLC22A1-3), the cation and carnitine transporters OCTN1 (SLC22A4), OCTN2 (SLC22A5) and OCT6 (SLC22A16), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

“…37 OCTN2 (SLC22A5) is another member of the SLC22 family of plasma membrane solute carrier proteins. 38 OCTN2 is expressed ubiquitously, with high expression in kidneys and lower expression in heart, skeletal muscles, and other tissues. 39 Mutations in this gene have been reported in a few patients with primary carnitine deficiency, 40,41 most of whom presented early in life with a severe metabolic decompensation.…”

Clonidine Transport at the Mouse Blood—Brain Barrier by a New H+ Antiporter that Interacts with Addictive Drugs

“…It could facilitate the entry of some amine drugs, such as propranolol, amphetamine, and nicotine, into the brain (Oldendorf et al, 1979;Pardridge et al, 1984;Pardridge and Connor, 1973). However, these earlier studies provided no information on the molecular and/or functional identity of this transporter, as evidence regarding this was obtained only recently (Koepsell et al, 2007). The carrier-mediated transport of DPH, which could involve the clonidine BBB transporter, was suggested to be present at the BBB and to work as an H + antiporter in Caco-2 cells (Au-Yeung et al, 2006;Goldberg et al, 1987;Mizuuchi et al, 2000).…”

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

“…BRB, blood-retina barrier; BBB, blood-brain barrier; pH e , extracellular vascular pH. and more specific Oct2/Oct1 inhibitors (guanidine, agmatine, and cisplatin) (Koepsell et al, 2007). All these compounds similarly and significantly reduced B1.7-fold the [ 3 H]-MPP + eye transport ( Figure 3B).…”

“…Many compounds inhibit/modulate transporters, although they are not necessarily themselves transported. Thus, Koepsell et al (2007) outlined a general strategy for discriminating between the functions of Oct transporters, but it does not appear to be applicable in vivo due to species differences and lack of extrapolation of transport parameters (K i /K m /V max ) usually obtained with transfected heterologous systems. Moreover, a combination of diverse overlapping transport systems with different affinities, such as uptake1 and uptake2, make it difficult to quantify individual transporter components.…”

“…If this is so, then uptake1/2 transporters could modulate the local availability of biogenic amine neurotransmitters by luminal (blood) and/or abluminal (nerve side) carrier systems. Uptake2 carriers could also transport many drugs and xenobiotics like 1-methyl-4-phenylpyridinium (MPP + ) (Koepsell et al, 2007).…”