Interaction of adriamycin aglycones with isolated mitochondria: Effect of selenium deficiency

Adriamycin (AdM) aglycones have dramatic effects on isolated heart mitochondria, oxidizing pyridine nucleotides, modifying sulfhydryl groups, and triggering a permeability transition of the inner membrane that results in free passage of solutes smaller than 1500 Da. In this investigation, the role of glutathione (GSH) peroxidase in these actions of the aglycones was evaluated, by comparing mitochondria from selenium-deficient and selenium-supplemented rats, with the following results. Selenium deficiency was without effect on the permeability transition of heart mitochondria, followed via Ca 2+ release and triggered by AdM aglycone or by t-butyl hydroperoxide (TBH) or H 2O 2, both of which are authentic substrates of the peroxidase. The permeability transitio of liver mitochondria was delayed by selenium deficiency regardless of the triggering agent; however, substantial triggering by the aglycone and TBH persisted in mitochondria from selenium-deficient animals. Selenium deficiency inhibited thiol modification elicited by AdM aglycone and H 2O 2 in heart mitochondria and by the aglycone, TBH, and possibly H 2O 2 in liver mitochondria. It would thus appear that AdM aglycone, TBH, and H 2O 2 can induce the permeability transition of isolated heart mitochondria via a process (or processes) distinct from the catalytic activity of the peroxidase. Furthermore, even in liver, where involvement of the peroxidase is observed, mechanisms other than the GSH cycle can contribute to transition induction by the agylcone and by TBH. Finally, mitochondrial -SH group modification by the aglycones appeared not be causally linked to induction of the permeability transition. This laboratory has suggested that the effects of aglycone metabolites of AdM on mitochondria mediate the cardiotoxicity that limits use of the parent drug. The data presented in this paper argue against the involvement of GSH peroxidase in that process. They are in agreement with in vivo studies, which have generally failed to find evidence for amelioration of AdM cardiotoxicity in selenium-deficient animals.