TY - JOUR T1 - Effects of Chlorpromazine on Glutamate Dehydrogenase JF - Molecular Pharmacology JO - Mol Pharmacol SP - 156 LP - 163 VL - 6 IS - 2 AU - L. A. FAHIEN AU - O. SHEMISA Y1 - 1970/03/01 UR - http://molpharm.aspetjournals.org/content/6/2/156.abstract N2 - Certain drugs which affect behavior, such as chlorpromazine, desipramine, imipramine, and amitriptyline, are inhibitors of glutamate dehydrogenase (EC 1.4.1.3). Of this group, chlorpromazine was found to be the most potent inhibitor. Chlorpromazine inhibits reactions with DPNH more than TPNH, mainly by increasing substrate inhibition with DPNH. Chlorpromazine has no effect on the reverse reaction with DPN and glutamate. This drug is not a competitive inhibitor of the coenzymes or substrates of the glutamate dehydrogenase reaction. The effect of chlorpromazine is almost completely abolished by ADP and GTP, but not ATP. These results suggest that chlorpromazine is bound to an allosteric site on the enzyme. Like GTP, chlorpromazine in the presence of DPNH produces dissociation of the enzyme. Chlorpromazine does not inhibit glutamine synthetase (EC 6.3.1.2) or the mitochondrial glutamate-oxalacetate transaminase (EC 2.6.1.1). On the basis of these results it seems likely that the inhibition of glutamate dehydrogenase by chlorpromazine could increase brain levels of glutamine in the presence of high levels of ATP and DPNH. When the levels of ADP and DPN are high chlorpromazine has little effect on glutamate dehydrogenase. Since the levels of glutamate dehydrogenase are high in brain, liver, and kidney mitochondria, and since many compounds of diverse structures are bound to glutamate dehydrogenase, this enzyme could possibly play a role in binding and consequently concentrating some drugs in the mitochondria. The kinetic properties of bovine heart, brain, and adrenal medulla glutamate dehydrogenase were found to be identical with those of the liver enzyme. These plus other experiments indicate that this enzyme is similar in these bovine organs. Similarly, the kinetic properties of bovine brain mitochondrial glutamate-oxalacetate transaminase are identical with those of the liver enzyme. ER -