Is superoxide an initiator of microsomal lipid peroxidation?

The effects of "pro-oxidant" quinones, doxorubicin, Fe(3+)-ADP-doxorubicin complex, and menadione, as well as of free radical scavengers possessing superoxide-dismuting activities, Fe(3+)-rutin and Cu(2+)-rutin, on superoxide production and lipid peroxidation in rat liver microsomes have been studied. All quinone compounds efficiently suppressed lucigenin-dependent chemiluminescence produced in NADPH-dependent microsomal lipid peroxidation, but exhibited different effects on cytochrome c reduction: doxorubicin and Fe(3+)-ADP-doxorubicin weakly inhibited and menadione enhanced it. In accord with previous findings, menadione inhibited malondialdehyde (MDA) formation in microsomes, while Fe3-ADP-doxorubicin enhanced it. Efficiency of inhibition of MDA formation by the Fe(3+)-rutin and Cu(2+)-rutin complexes correlated well with their superoxide-dismuting activities in contrast to the findings obtained in nonenzymatic liposomal peroxidation, where the formation of superoxide ion is not expected. On these grounds, we propose that superoxide ion is an obligatory initiation species in microsomal lipid peroxidation; the effects of pro-oxidant quinones on lipid peroxidation depends on their ability to chelate iron ions and not on their redox-cycling activities.

Mechanism of the interaction of superoxide ion and ascorbate with anthracycline antibiotics.

The interaction of superoxide ion and ascorbate anion with anthracycline antibiotics (adriamycin and aclacinimycin A) as well as with their Fe3+ complexes has been studied in aprotic and protic media. It was found that both superoxide and ascorbate reduce anthracyclines to deoxyaglycons via a one-electron transfer mechanism under all conditions studied. The reaction of ascorbate anion with adriamycin and aclacinomycin A in aqueous solution proceeded only in the presence of Fe3+ ions; it is supposed that an active catalytic species was Fe3+ adriamycin. It is also supposed that the reduction of anthracycline antibiotics by O2-. and ascorbate in cells may increase their anticancer effect.

[Mechanism of the interaction of the anticancer antibiotic adriamycin (doxorubicin) with the anion radical O2]. / Issledovanie mekhanizma vzaimodeistviia protivorakovogo antibiotika adriamitsina (doksorubitsina) s anion-radikalom O2..

Interaction of the O2. anion radical with adriamycin in water-acetonitrile mixtures was studied by UV-spectroscopy. It was shown that with changing of the water content in the reaction mixture from 0 to 90 per cent O2. practically irreversibly reacted with adriamycin to form the same product. The spectrum of the reaction product was shifted to the long-wave region as compared to that of adriamycin and depended on the solvent composition. In the presence of the proton donors the "regeneration" of the absorption spectrum of the starting antibiotic was observed. To investigate the mechanism of the reaction product formation, electrochemical reduction of adriamycin and its reaction with benzosemiquinone and alkali were studied. Formation of the same compound under the different conditions showed that the primary step of O2. interaction with adriamycin was one electron reduction of the antibiotic. The study suggested the reaction mechanism involving formation of adriamycin semiquinone as a result of the electron transfer from the O2. molecule, splitting out of the sugar moiety and reduction of deoxyaglycone semiquinone into anion of deoxyaglycone tautomer. The possible role of the oxygen anion radical in the mechanism of activation of adriamycin and other anthracycline antibiotics is discussed.