Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase,product of a susceptibility gene for schizophrenia |
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Authors: | Sanae Iwana Tomoya Kawazoe Hwan KI. Park Koichiro Tsuchiya Koji Ono Kazuko Yorita |
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Affiliation: | 1. The Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan;2. Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan |
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Abstract: | D-Amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (Ki = 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug. |
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Keywords: | smallcaps smallerCapital" >D-Amino acid oxidase schizophrenia chlorpromazine oligomer glutamatergic neurotransmission inhibition |
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