Chloroquine is a potent inhibitor of glutamate dehydrogenase in liver and kidney-cortex of rabbit

The effect of chloroquine and other antimalarial drugs on glutamate dehydrogenase activity was studied in liver and renal mitochondria as well as in kidney-cortex tubules of rabbit. In permeabilized mitochondria, with free access of substrates and drugs to glutamate dehydrogenase, 100 mu M chloroquine decreased both glutamate synthesis and glutamate deamination by about 70 and 50%, respectively. K-i value was equal to 49 mu M in both liver and renal mitochondria. Other antimalarials (amodiaquine, quinacrine, chinidine and chinine) showed much smaller effect on the enzyme activity. Both ADP and L-leucine, allosteric activators of glutamate dehydrogenase, did not abolish the inhibitory action of chloroquine. Moreover, when added at 200 mu M concentrations all drugs besides chinine suppressed glutamate formation in kidney-cortex tubules while chloroquine and quinacrine inhibited also glutamate deamination. Furthermore, chloroquine at 500 mu M concentration decreased significantly [C-14]glutamate transport into kidney-cortex mitochondria. In view of these observations it seems likely that chloroquine and some other antimalarials may inhibit the rate of glutamate metabolism in both liver and kidney-cortex causing hepatoxicity and nephrotoxicity. A possible action of chloroquine as an inhibitor of glutamate dehydrogenase in Plasmodium falciparum during the clinical treatment of malaria is discussed. (C) 1997 The Italian Pharmacological Society.