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Abstract
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, 100μMchloroquine decreased both glutamate synthesis and glutamate deamination by about 70 and 50%, respectively. Kivalue was equal to 49μMin both liver and renal mitochondria. Other antimalarials (amodiaquine, quinacrine, chinidine and chinine) showed much smaller effect on the enzyme activity. Both ADP andL-leucine, allosteric activators of glutamate dehydrogenase, did not abolish the inhibitory action of chloroquine. Moreover, when added at 200μMconcentrations all drugs besides chinine suppressed glutamate formation in kidney-cortex tubules while chloroquine and quinacrine inhibited also glutamate deamination. Furthermore, chloroquine at 500μMconcentration decreased significantly [14C]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 inPlasmodium falciparumduring the clinical treatment of malaria is discussed.
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