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Inhibitory Effects of Human Glutamate Dehydrogenase Isozymes by Antipsychotic Drugs for Schizophrenia
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 Title & Authors
Inhibitory Effects of Human Glutamate Dehydrogenase Isozymes by Antipsychotic Drugs for Schizophrenia
Nam, A-Reum; Kim, In-Sik; Yang, Seung-Ju;
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Glutamate is one of the major excitatory neurotransmitters in the central nervous system of vertebrates. Human GDH (hGDH) is the enzyme that regulates the glutamate metabolism and its expression is higher in the brains of schizophrenia patients than in normal subjects. This study examined the changes in the hGDH enzymatic activity caused by antipsychotic drugs (haloperidol, risperidone, ()-sulpride, chlopromazine hydrochloride, melperone, ()butaclamol, domperidone, clozapine) related to schizophrenia. First of all, hGDH isozymes (hGDH1, hGDH2) were synthesized by genetic recombination. As a result of the enzyme assay, haloperidol, ()-sulpride, melperone and clozapine had an inhibitory effect on the hGDH isozymes. In addition, haloperidol showed a non-competitive inhibition against the substrate, 2-oxoglutarate. In contrast, it showed an uncompetitive inhibition against another substrate, NADH. The inhibitory effect of haloperidol on hGDH2 was abolished by the presence of L-leucine, an allosteric effector of hGDH, but by not other antipsychotic drugs. These results revealed the inhibition of enzyme activity by psychotropic drugs in hGDH isoenzymes (hGDH1 and hGDH2) and the possibility that haloperidol may be used to regulate the GDH activity and glutamate concentration in the central nervous system.
Antipsychotic drug;Glutamate;Human Glutamate Dehydrogenase (hGDH);Isozyme;Non-competitive inhibition;Schizophrenia;Uncompetitive inhibition;
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