Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity.

The absorption, distribution and excretion of most of xenobiotics, drugs, environmental toxins and their metabolites are mediated by membrane transporters. Recent advances in the transporter molecular biology have made it possible to investigate the mechanisms of transport of those exogenous compounds and their transporter-mediated toxicity at the molecular level. Exogenous compounds including drugs and toxic substances occurring in the environment pass through the transporters with broad substrate selectivity, namely "multispecific" transporters, taking advantage of the multispecific nature to exert their toxic effects. The remarkable examples of such transporter-mediated toxicity are 1-methyl-4-phenyl-2,3-dihydropyridinium (MPP+)-neurotoxicity mediated by dopamine transporters, cephaloridine-nephrotoxicity mediated by organic anion transporters and methylmercury-toxicity mediated by system L amino acid transporters. The molecular identification of system L transporter LAT1 (L-type amino acid transporter 1) has lead to the understanding of the mechanisms of their multispecific substrate recognition and revealed their localization at the blood-brain barrier and placental barrier. LAT1 relies on the hydrophobic interaction between substrate amino acid side chains and the substrate binding site, so that many variations are possible for the substrate amino acid side chains, which is the basis of the broad substrate selectivity. System L transporters, thus, function as a path for the membrane permeation of drugs and toxic compounds occurring in the environment with amino acid-related structures. Beside methylmercury-cysteine conjugate, amino acid-related neurotoxins such as beta-N-methylamino-L-alanine, S-(1,2-dichlorovinyl)-L-cysteine and 3-hydroxykynurenine are proposed to pass through system L transporters to exert their toxicity. Because the presence of such transporters is crucial for the manifestation of the organ toxicity, the inhibition of the transporters would be expected to be beneficial to prevent the disorders caused by the transporter-mediated toxicity.