Role of the cardiolipin-adriamycin complex in mitochondrial toxicity

It is demonstrated here that adriamycin (ADM), a widely used antimitotic agent, has a similar affinity for its target (DNA) and for a mitochondrial membrane component (cardiolipin). This cardiolipin—adriamycin complex is responsible for the inhibition of cytochrome c oxidase. The activity change of cytochrome oxidase evaluated for several adriamycin derivatives in beef heart mitochondria indicates that the inhibition is not a consequence of a direct drug—enzyme interaction but of a modification of the enzyme lipid environment. The adriamycin—cardiolipin complex segregates in a separate lipid phase and the new enzyme environment does not allow its activation. Cardiolipin (CL) is essential for cytochrome c oxidase activity. This inactivation could explain the adriamycin cardiotoxicity. Indeed, it is significant that the most cardiotoxic adriamycin derivatives form the strongest complexes with cardiolipin. A precise knowledge of this inhibition mechanism is a prerequisite for the synthesis of new non-cardiotoxic compounds.