Na+-dependent carnitine transport by organic cation transporter (OCTN2): Its pharmacological and toxicological relevance

Carnitine deficiency, either primary or drug-induced, causes critical sympt oms and is thought to involve alteration of active transport of carnitine a cross the plasma membrane of tissues as the underlying mechanism. Recently, we showed that human organic cation transporter, hOCTN2, cloned as a membe r of the organic cation transporter family, is a physiologically important Na+-dependent high-affinity carnitine transporter in humans. In this study, we further characterized the functional properties of hOCTN2 and examined the interaction between hOCTN2-mediated carnitine transport and clinically used drugs to assess possible toxicological effects. When expressed in huma n embryonic kidney (HEK)293 cells, hOCTN2 showed low but significant stereo specific transport activity: D-carnitine was transported with lower affinit y (K-m = 10.9 mu M) than the L-isomer (K-m = 4.3 mu M). One Na+ appeared to be associated with the transport of one carnitine molecule. hOCTN2-mediate d transport of acetyl-L-carnitine was also Na+-dependent and of high affini ty, with a K-m value of 8.5 mu M. To examine the transport activity for org anic cations other than carnitine and the possible relationship of drug-ind uced carnitine deficiency with hOCTN2, the inhibitory effect of several dru gs on hOCTN2-mediated L-carnitine transport was examined. Many zwitterionic drugs, such as cephaloridine, and many cationic drugs, such as quinidine a nd verapamil, exhibited significant inhibitory effects. Among these inhibit ors, tetraethylammonium, pyrilamine, quinidine, verapamil, and valproate we re found to be transported by hOCTN2. The results suggest that the carnitin e deficiency-related toxicological effects by long-term treatment with such drugs might be ascribed to a functional alteration of hOCTN2-mediated carn itine transport.