Doxorubicin and doxorubicinol-induced alterations in human polymorphonuclear leukocyte oxygen metabolite generation

The effects of doxorubicin and its primary metabolite doxorubicinol on the polymorphonuclear leukocyte (PMNL) respiratory burst were studied using lucigenin and luminol for detection of oxygen metabolite generation. Although both anthracyclines inhibited PMNL activation at concentrations achieved with therapeutic administration of doxorubicin, doxorubicinol was much more potent than doxorubicin. Preincubation of PMNL with either drug caused a persistent inhibition of cell function after drug washout that was not prevented by inclusion of either free radical scavengers or iron chelators in the incubation medium. Although complete suppression of the PMNL respiratory burst occurred with concentrations of doxorubicinol greater than 0.3 microgram/ml, a marked potentiation of the response was observed at lower concentrations (0.01 or 0.03 microgram/ml) of the same drug. Potentiation occurred only when albumin was present in the reaction medium, was eliminated by iron chelators, was not observed after PMNL incubation with drug and was dependent upon the activating agent. In contrast to doxorubicinol, doxorubicin did not potentiate the PMNL respiratory burst. These results demonstrate potent effects of doxorubicinol on PMNL oxygen metabolite generation that are markedly greater in degree and different in character than those of doxorubicin. Because both inhibitory and enhancing effects are apparent at concentrations of doxorubicinol achieved in vivo, this metabolite may be important in the clinically observed toxicity of doxorubicin.