STUDIES FOR THE MECHANISM OF MULTIPLICITY IN SUBSTRATE SPECIFICITY OF TRANSPORTERS.

药代动力学特性对药物治疗具有重要意义，受结合蛋白、药物代谢酶和膜转运蛋白等多种因素的影响。其中，药物转运体对药物的肠道吸收、组织分布以及肝脏和肾脏排泄具有重要作用。因此，哪种药物被接受为每种转运体的底物将是重要的。然而，一些药物转运体接受多种化合物作为底物，其多特异性机制尚未明确。有机阳离子/肉毒碱转运体OCTN和有机阴离子转运多肽otp - c也接受多种生理和药物化合物作为底物。在本研究中，我们通过关注moctn转运肉碱作为生理底物和阳离子化合物的多功能性来研究这些转运体识别底物的多特异性机制。OCTN在转运肉碱时，完全依赖Na^+，而有机阳离子如四乙基铵（TEA）的转运则不依赖Na^+。利用OCTN突变蛋白的研究表明，肉碱和TEA在OCTN2上部分共享底物识别位点，但它们并不完全相同。Na^+在很大程度上影响了肉碱对OCTN2的亲和力，而TEA对Na^+对OCTN2的亲和力没有影响。然而，肉碱和茶表现出相互抑制作用，但不能用完全竞争抑制动力学来解释。肉毒碱与TEA之间转运机制的差异可以解释为肉毒碱特有的羧基片段的存在，Na^+影响肉毒碱羧基片段与OCTN2蛋白之间的相互作用。这些观察结果表明，OCTN的多特异性是由于OCTN的多功能性，根据底物改变转运机制，至于驱动力Na^+。因此，阐明转运蛋白对每种底物的驱动力对于阐明转运蛋白的多特异性机制具有重要意义。就OATP而言，目前还没有明确的驱动力证明，而OATP接受各种化合物作为底物。为了阐明OATP多特异性的机制，在未来的研究中，有必要确定每种底物的驱动力

Pharmacokinetic characteristics are important for the adequate drug therapy and they are affected by many factors, including binding proteins, drug metabolizing enzymes and membrane transporters. Among them, drug transporter are important for the intestinal absorption, tissue distribution, and hepatic and renal excretion of drugs. Accordingly, it will be important what kinds of drugs are accepted as substrates for each transporter. However, some drug transporters accept various compounds as substrates and it has not been clarified the mechanism for such multispecificity of drug transporterOrganic cation/carnitine transporter OCTN and organic anion transporting polypeptide OATP-C also accept various physiological and drug compounds as substrates. In the present study, we studied the mechanism for the multispecificity in the substrate recognition of those transporters by focusing on the multifunctionality of themOCTN transports carnitine as physiological substrates and cationic compounds … More as xenobiotics. When OCTN transports carnitine, it exclusively shows Na^+-dependence, while the transport of organic cation such as tetraethylammonium (TEA) is Na^+-independent. The study using mutant protein of OCTN exhibited that carnitne and TEA partially shares the substrate recognition sites on OCTN2, while they are not identical. Na^+ largely affect the affinity of carnitine to OCTN2, while TEA did not show any change in the affinity to OCTN2 by Na^+. However, carnitine and TEA exhibited mutual inhibitory effect, while they are not explained by complete competitive inhibition kinetics. The difference in the transporting mechanism between carnitine and TEA could be explained by the presence of the carboxylmoiety that is specific for carnitine and the Na^+ affect the interaction between carboxylmoiety of carnitine and OCTN2 protein. These observations suggested that multispecificity of OCTN is due to the multifunctionality of OCTN by changing the transport mechanisms depending on the substrates, regarding the driving force, Na^+. Accordingly, clarification of the driving force of the transporter for each substrate is important to clarify the mechanism of multispecificity of transporters. In the case of OATP, at present no driving force has been clearly demonstrated, while OATP accept various compounds as substrates. To clarify the mechanism for the multispecificity of OATP, it will be essential to identify the driving force for each substrate in future Less