Doxorubicin semiquinone radical

Pre-treatment with 70 mg AD 20 per kg 15 min before the injection of doxorubicin almost completely restored these activities (Praet et al. 1988). A20 is a W-acyldehydroalanine compound capable of stabilising the doxorubicin semiquinone radical as a consequence of its capto-dative properties. 

The structure of doxorubicin includes a quinone moiety therefore, it can easily accept an electron and undergo redox cycling (Fig. 7.47). Because it accumulates in the mitochondria, it can accept electrons from the electron transport chain and divert them away from complex I. It becomes reduced to the semiquinone radical in the process. This will then reduce oxygen to superoxide and return to the quinone form (Fig. 7.47). This could lead to oxidation of GSH and mtDNA. The subsequent damage may lead to the opening of the mitochondrial permeability transition pore. Consequently, mitochondrial ATP production will be compromised, and ATP levels will decline. 

Scheme Mechanism of free radical generation by doxorubicin. The quinone form accepts an electron to yield the semiquinone free radical, which returns to the quinone by giving an electron to molecular oxygen to form the superoxide anion. Modified from [49].

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

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