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Drug Metab Dispos. 2018 Jun;46(6):779-785. doi: 10.1124/dmd.118.080440. Epub 2018 Mar 12.

Substrate Selectivity Check of the Ergothioneine Transporter.

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Department of Pharmacology, University of Cologne, Cologne, Germany.
Department of Pharmacology, University of Cologne, Cologne, Germany


The candidate vitamin ergothioneine (ET) is a unique antioxidant. Expression of the ET transporter (ETT) (gene symbol SLC22A4) in distinct cells is thought to signal intracellular ET activity, since we have previously shown that the ETT is highly selective for ET. Unfortunately, some continue to hold the ETT as a relevant drug transporter, using the misleading functional name OCTN1, novel organic cation transporter. The present study was provoked by two recent reports in which new ETT substrates were declared. Astonishingly, the transport efficiencies (TEs) of ETT for saracatinib and some nucleoside drugs were as high as the TE for ET. Here we examined, based on regulated expression of ETT from human and rat in 293 cells and liquid chromatography-mass spectrometry quantification, the transport of several drugs. With the nucleosides cytarabine, gemcitabine, 2'-deoxycytidine, and 2'-deoxyadenosine, and the drugs saracatinib, ipratropium, metformin, and oxaliplatin, the uptake into cells expressing ETT was not increased over control cells. ETT-mediated uptake of gabapentin was detectable, but the TE was approximately 100-fold lower than the TE for ergothioneine (50-200 µl/min per milligram of protein). In conclusion, the ETT remains highly specific for its physiologic substrate ergothioneine. Our results contradict several reports on additional substrates. The ETT does not provide multiple substrate specificities, and it is not a transporter of cationic drugs. Only compounds that are related to ET in substructure-for example, gabapentin, carnitine, and TEA-can be transported, but with very low efficiency. Thus, ETT persists as a specific molecular indicator of ET activity.


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