Adriamycin and its iron(III) and copper(II) complexes. Glutathione-induced dissociation; cytochrome c oxidase inactivation and protection; binding to cardiolipin.

Some reactions of adriamycin (doxorubicin) and its Fe3+ and Cu2+ complexes were investigated with a view to understanding the mechanisms by which metal ion-adriamycin complexes damage cellular components. The ability of adriamycin in the presence of Cu2+ to inactivate the mitochondrial enzyme cytochrome c oxidase was effectively prevented by physiologic levels of glutathione. This result is explained by the observation that glutathione reacts with the Cu2+-adriamycin complex to produce free adriamycin. As sulfhydryl compounds are, in contrast, known to promote Fe3+-adriamycin-induced damage to cellular components, these results suggest that the response of a metal ion-adriamycin system to the presence of sulfhydryl compounds may be indicative of whether or not Cu2+-adriamycin is the damaging species. The partition of adriamycin into the octanol phase of an octanol-water two-phase system was greatly enhanced by the presence of cardiolipin. This result can be explained by the formation of a strong adriamycin-cardiolipin complex in the octanol phase which is one-half formed at an adriamycin concentration of 6 microM.