Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues

Abstract

Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyladriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14- O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.