title: The carnitine transporter SLC22A5 is not a general drug transporter, but it efficiently translocates mildronate.
abstract: In addition to its function as carnitine transporter, novel organic cation transporter type 2 (OCTN2; human gene symbol SLC22A5) is widely recognized as a transporter of drugs. This notion is based on several reports of direct measurement of drug accumulation. However, a rigorous, comparative, and comprehensive analysis of transport efficiency of OCTN2 has not been available so far. In the present study, OCTN2 orthologs from human, rat, and chicken were expressed in 293 cells using an inducible expression system. Uptake of trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide (ASP(+)), cephaloridine, ergothioneine, gabapentin, mildronate, pyrilamine, quinidine, spironolactone, tetraethylammonium, verapamil, and vigabatrin was determined by liquid chromatography/mass spectrometry. For reference, uptake of carnitine was measured in parallel. Our results indicate that OCTN2-mediated uptake of drugs was not significantly different from zero or, with tetraethylammonium and ergothioneine, was minute relative to carnitine. The carnitine congener mildronate, by contrast, was transported very efficiently. Thus, OCTN2 is not a general drug transporter but a highly specific carrier for carnitine and closely related molecules. Transport parameters (cellular accumulation, transporter affinity, sodium dependence) were similar for mildronate and carnitine. Efficiency of transport of mildronate was even higher than that of carnitine. Hence, our results establish that OCTN2 is a key target of the cardioprotective agent mildronate because it controls, as integral protein of the plasma membrane, cellular entry of mildronate and enables efficient access to intracellular targets. The highest levels of human OCTN2 mRNA were detected by real-time reverse transcription-polymerase chain reaction in kidney, ileum, breast, small intestine, skeletal muscle, and ovary but also in some heart and central nervous system tissues.
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Grigat
authors.forename: Christian
authors.initials: C
authors.lastname: Fork
authors.forename: Markus
authors.initials: M
authors.lastname: Bach
authors.forename: Stefan
authors.initials: S
authors.lastname: Golz
authors.forename: Andreas
authors.initials: A
authors.lastname: Geerts
authors.forename: Edgar
authors.initials: E
authors.lastname: Schömig
authors.forename: Dirk
authors.initials: D
authors.lastname: Gründemann
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D002331:Carnitine / Q000378:metabolism*; D002645:Chickens; D019976:Cloning, Organism; D005260:Female; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008763:Methylhydrazines / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D000074058:Solute Carrier Family 22 Member 5
chemical_list: D026901:Membrane Transport Proteins; D008763:Methylhydrazines; D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002331:Carnitine