Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia

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 (K_i = 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.

Keywords::

• D-Amino acid oxidase
• schizophrenia
• chlorpromazine
• oligomer
• glutamatergic neurotransmission
• inhibition

Acknowledgements

We are grateful to Dr. H. Uchida (Agilent Technologies Japan, Ltd., Tokyo, Japan) for the courtesy of his conducting detailed analyses in ESI-TOF-MS. We also wish to thank Mr. K. Kodama and Mr. A. Nishigami for their help with the measurement of the NMR spectra and helpful discussions. We extend our deepest thanks to Dr. H. Takiwaki and Dr. E. J. Jung for helpful comments and information. This work was supported by a grant for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan.