Organic Cation Transporters: Physiology, Toxicology and Special Focus on Ethidium as a Novel Substrate

The polyspecific organic cation transporters OCT1 (SLC22A1), OCT2 (SLC22A2) and OCT3 (SLC22A3) mediate facilitated and bidirectional diffusion of small (≤ 500Da) organic cations with broad specificities for endogenous substrates such as choline, acetylcholine and monoamine neurotransmitters, as well as a variety of xenobiotics. Importantly, besides a wide range of clinically used drugs, these also include several toxins like the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and herbicide paraquat. OCT2-OCT3 display differential tissue distribution: OCT1 is predominantly found in liver of humans, and liver and the kidney in rodents; OCT2 is most strongly expressed in both human and rodent kidney, whereas OCT3 primarily expressed in placenta, but also more widely detected in various tissues, including brain and lung. The physiological roles OCTs as transporters for biogenic amines or acetylcholine in these tissues are still debated, in contrast to their involvement in providing access pathways for harmful/toxic cationic substrates into the body and particular tissues. This review highlights a novel role of human and rodent OCTs as carriers of the toxic fluorescent dye ethidium, as opposed to the less harmful related phenanthridine compound propidium, which is not transported. Additional uptake and efflux pathways for ethidium in pro- and eukaryotes are discussed. OCT-mediated pathways may determine major entry routes for ethidium into the body where toxicity via specific mechanisms may develop in tissues expressing OCTs. Considering the high affinity of OCTs for ethidium (Km = 1-2 μM) and their strong expression in various organs, strict safety guidelines for the handling of ethidium should be reinforced.