Bioenergetics in clinical medicine: prevention by forms of coenzyme Q of the inhibition by adriamycin of coenzyme Q10-enzymes in mitochondria of the myocardium.

Abstract

Adriamycin inhibits the succinoxidase system and the NADH-oxidase system. Both of the intact mitochondrial enzymes and the pentane-extracted preparations are inhibited. The inhibition can be prevented by a molar ratio of coenzyme to adriamycin of 3:1 for coenzyme QIo (ubiquinone) Adriamycin and related anthracyclines are now widely used in clinical medicine for the chemotherapy of cancer (1). Carter and Blum (2) summarized the wide range of clinical antitumor activities and the integration of adriamycin into combined modality protocols. The clinical use of adriamycin is accompanied by serious side-effects, which rigidly restrict its use. Although cardiotoxicity is the most serious side-effect in cancer patients, there is a spectrum of other major side-effects, including hematologic toxicity. The biochemical elucidation of the mechanism (3) of these side-effects, particularly the cardiotoxicity, has become urgent, and particularly if such knowledge could minimize side-effects.We have considered that the cardiotoxicity of adriamycin might be due to inhibition of coenzyme Q1o-enzymes. Data have now been obtained on four forms of coenzyme Q (CoQ) that show that the coenzymes prevent this inhibition in vitro. The biochemical basis of this study of cardiotoxicity is the knowledge that coenzyme Qio (ubiquinone) is an indispensable component of the succinoxidase and the NADH-oxidase systems and other CoQi0-enzymes which are essential to the electron transfer mechanism and oxidative phosphorylation ("bioenergetics") of mitochondria of the human myocardium. Inhibition (toxicity) of enzymes of respiration could be damaging to the heart, and could range from a minor to a major component of the cardiotoxicity of adriamycin. METHODS The methods for these assays with adriamycin, the two aglycones, and the four forms of coenzyme Q have been reported (4). Preparation of beef heart mitochondria (5) and extraction with pentane (6) were described. The determination of the specific activities of succinoxidase and NADH-oxidase, inhi-

Resistance to adriamycin cytotoxicity among respiratory-deficient mutants in yeast

“…(12). Subsequently, coenzyme Qlo has been used to prevent the inhibition by Adriamycin of coenzyme Qlo enzymes and to partially prevent the cardiotoxic side effect of the drug in animal studies (7,14 (9), using rat liver microsomes and Adriamycin. Free-radical production by Adriamycin in animal cells and ensuing lipid peroxidation have been suggested as possible contributing factors for cardiac damage by Adriamycin (25).…”

Toxic Mechanisms of the Heart: A Review*

“…Decreased mitochondrial respiratory control reflecting a decrease in the maximum oxidative capacity was reported by Ferrero and coworkers (46). Folkers et al showed that doxorubicin inhibits the succinate dehydrogenasecoenzyme Q reductase and the NADH oxidase-coenzyme Q reductase systems of beef heart mitochondria (85,86). More recently, Goormaghtigh and his coworkers, and others have shown that doxorubicin inhibits cytochrome c oxidase by binding with and removing the mitochondrial membrane cardiolipin necessary for mitochondrial enzyme function (59,60,124).…”

Statins, coenzyme Q10 and diabetes type 2

“…Such a decrease was observed both in experimental animals (2) and humans (3). It was suggested that a defi ciency of Q10 in the pancreas could impair bioenergetics, the generation of ATP, and the biosynthesis of insulin (4). In diabetes, CoQ 10 defi ciency may be linked to impaired beta-cell function and the development of insulin resistance (5).…”