10. 脳のグルタミン酸脱水素酵素に対する各種向精神薬の影響

抄録

Although glutamic dehydrogenase (EC 1. 4. 1. 3) was considered to play an important role in the brain, the properties of this enzyme have remained unknown. Thus, glutamic dehydrogenase was purified from rat brain mitochondria by the method described in the legend to Fig. 1, and its properties were studied. Biochemical properties of rat brain glutamic dehydrogenase, such as pH optimum, Km values for the substrates, cofactor requirements and inhibition by estrogenic steroids, were identical with those of bovine liver glutamic dehydrogenase. In this paper are reported the inhibitory actions of psychotropic drugs on brain glutamic dehydrogenase, whereby 50 per cent inhibitions were obtained to correlate their central nervous effects with their inhibition of enzyme activity.
1) Intensity of their inhibition appeared to depend on concentration of enzyme protein. As shown in Fig. 2, there was a more intense inhibition of the reaction at lower protein concentrations.
2) The inhibitory actions of the psychotropic drugs were compared by obtaining 50 per cent inhibitions. As shown in TABLE I, the major tranquillizers had the most potent inhibitory actions, though the minor tranquillizers or antidepressants inhibited glutamic dehydrogenase to a lesser extent. Among the major ones, butyrophenone derivatives, in the form of haloperidol and triperidol, were found to be the most potent. Next to them, trifluoperazine and perphenazine (phenothiazine derivatives) were potent inhibitors. Oxypertine and clotiapine, which were fundamentally different in their chemical structures from the butyrophenone and phenothiazine derivatives, inhibited the reaction to a greater extent than chlorpromazine, perazine, fluphenazine and levomepromazine (phenothiazine derivatives). Thus the chemical structures of the psychotropic drugs were not.correlated with their inhibition of glutamic dehydrogenase. However, the evidences referred to in the TABLE I suggested that there might be a correlation between inhibition of the enzyme activity in vitro and central nervous system effects in vivo. Liver glutamic dehydrogenase, purified by the same method as described in brain, was also inhibited to the same degree with the brain enzyme by each psychotropic drug.
3) Anticonvulsants, convulsants, biogenic amines and their antagonists had no or little effects on glutamic dehydrogenase.
4) The inhibitory actions of psychotropic drugs could be prevented or reversed by addition of ADP. These results suggest that the glutamic dehydrogenase inhibitions by psychotropic drugs may be of an allosteric nature.