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Received for publication May 2, 2006.
Revised August 11, 2006.
Accepted for publication August 21, 2006.
We have cloned and functionally characterized the rat orthologue of multidrug and toxin extrusion type transporter 1 (rMATE1). The mRNA of rMATE1 was strongly expressed in kidney, and detectable in the various tissues such as brain, stomach, colon, lung, liver, spleen, skeletal muscle and prostate. When stably expressed in HEK293 cells, rMATE1 could mediate the transport of TEA and cimetidine under the condition where the membrane potential was disrupted by a high concentration of potassium ion and intracellular pH was reduced by NH4Cl pretreatment. When extracellular pH was changed from 5.5 to 8.5, the transport of TEA by rMATE1 was greatest at pH 7.5. Kinetic analyses showed that the transports of TEA and cimetidine mediated by rMATE1 were both saturable with the Km of 260 ± 10 and 3.01 ± 0.21 µM, respectively. It was found that cimetidine is the most potent inhibitor of rMATE1, and many other organic cations, such as MPP, amiloride, imipramine and quinidine, are also effective as inhibitors. Pretreatment of the cells expressing rMATE1 with pCMBS significantly reduced TEA transport, but this effect was totally reversed by subsequent treatment with DTT. These results indicate the functional nature of rMATE1 is consistent with that of the hypothetical organic cation/ H+ antiporter system in the brush border membrane of the renal tubular epithelial cells. Accordingly, these results suggest that rMATE1 is an electroneutral and multispecific organic cation transporter energized by the trans-proton gradient, and plays a physiological role in renal secretion of organic cations, including cationic drugs clinically used.
Key words:
drug disposition, drug efflux, drug secretion, drug-drug interactions, multi-drug resistance, organic cation transport, renal disposition, renal elimination, renal toxicity, renal transport
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