| Co-Investigator(Kenkyū-buntansha) |
SAI Yoshimichi Kanazawa University, Graduate School, Assistant Professor, 大学院・薬学研究科, 助手 (40262589)
TSUJI Akira Kanazawa University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (10019664)
HAGA Makoto Tokyo University of Science, Pharmaceutical Sciences, Associate Prof., 薬学部, 助教授 (70110666)
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| Research Abstract |
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 transporter
Organic 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 them
OCTN transports carnitine as physiological substrates and cationic compounds
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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
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