A ‘hexokinase effect’ in the inhibition of oxidative phosphorylation in heart muscle mitochondria by Adriamycin

Muhammed, H; Ramasarma, T.; Kurup, C. K. Ramakrishna

doi:10.1016/0006-291x(82)90949-4

Cited by 8 publications

(2 citation statements)

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“…Importantly, the concentrations of doxorubicin which we now show cause non-oxidative inactivation ofelectron transport in SMP are similar to those which have been shown to cause inhibition of oxidase activities in intact mitochondria [3,5,25,26]. Lower concentrations of doxorubicin effectively inhibit succinate oxidation in intact mitochondria [13,14,26] but this cannot be due to inactivation of the succinate oxidase pathway itself, since no effect is observed in broken mitochondria or SMP [13]. Unfortunately, we have no explanation for the-high doxorubicin sensitivity of cytochrome c oxidase reported by Goormaghtigh et al [12].…”

Section: Discussionsupporting

confidence: 78%

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Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin

Marcillat

Zhang

Davies

1989

Biochemical Journal

137

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The quinonoid anthracycline, doxorubicin (Adriamycin) is a potent anti-neoplastic agent whose clinical use is limited by severe cardiotoxicity. Mitochondrial damage is a major component of this cardiotoxicity, and rival oxidative and non-oxidative mechanisms for inactivation of the electron transport chain have been proposed. Using bovine heart submitochondrial preparations (SMP) we have now found that both oxidative and non-oxidative mechanisms occur in vitro, depending solely on the concentration of doxorubicin employed. Redox cycling of doxorubicin by Complex I of the respiratory chain (which generates doxorubicin semiquinone radicals, O2-, H2O2, and .OH) caused a 70% decrease in the Vmax. for NADH dehydrogenase during 15 min incubation of SMP, and an 80% decrease in NADH oxidase activity after 2 h incubation. This inactivation required only 25-50 microM-doxorubicin and represents true oxidative damage, since both NADH (for doxorubicin redox cycling) and oxygen were obligatory participants. The damage appears localized between the NADH dehydrogenase flavin (site of doxorubicin reduction) and iron-sulphur centre N-1. Succinate dehydrogenase, succinate oxidase, and cytochrome c oxidase activities were strongly inhibited by higher doxorubicin concentrations, but this phenomenon did not involve doxorubicin redox cycling (no NADH or oxygen requirement). Doxorubicin concentrations of 0.5 mM were required for 50% decreases in these activities, except for cytochrome c oxidase which was only 30% inhibited following incubation with even 1.0 mM-doxorubicin. Our results indicate that low concentrations of doxorubicin (50 microM or less) can catalyse a site-specific oxidative damage to the NADH oxidation pathway. In contrast, ten-fold higher doxorubicin concentrations (or more) are required for non-oxidative inactivation of the electron transport chain; probably via binding to cardiolipin and/or generalized membrane chaotropic effects. The development of agents to block doxorubicin toxicity in vivo will clearly require detailed clinical studies of doxorubicin uptake in the heart.

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Section: Discussionsupporting

confidence: 78%

“…Studies with cultured cardiac cells have shown that doxorubicin affects both ATP and phosphocreatine levels [9]. At the mitochondrial level, impairment of several bioenergetic functions has been reported [3][4][5][12][13][14]26,28].…”

Section: Introductionmentioning

confidence: 99%