A possible mechanism of adriamycin cardiotoxicity. Inhibition of NADP-linked isocitrate dehydrogenase.

In heart muscle, NADP-linked isocitrate dehydrogenase activity is particularly high when compared with that of the other representative NADPH-generating enzyme, glucose-6-phosphate dehydrogenase. Approximately 80% of cardiac NADP-linked isocitrate dehydrogenase activity originates in the mitochondria. Adriamycin inhibited the activity of both mitochondrial and cytoplasmic NADP-linked isocitrate dehydrogenase dose dependently but had no effect on glucose-6-phosphate dehydrogenase. The inhibition was kinetically distinguished as noncompetitive. Preincubation of crude cardiac enzyme preparations with adriamycin enhanced the inhibition time dependently for 45 min. However, there was no evidence to suggest that the metabolites of adriamycin produced in this system were active as inhibitors. Adriamycin-binding protein was fractionated by affinity chromatography, but NADP-linked isocitrate dehydrogenase activity was not detected in this fraction.