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The action of flavonoids on bovine leukemia virus‐transformed lamb fibroblasts (line FLK) and HL‐60 cells was accompanied by lipid peroxidation, their toxicity was partly prevented by iron chelator desferrioxamine and antioxidant N,N′‐diphenyl‐p‐phenylene diamine. This pointed out to the involvement of oxidative stress in flavonoid cytotoxicity. The concentration of compound for 50% survival of FLK cells (cL50) did not show correlation with Polarographic oxidation half‐peak potential (Ep/2) and/or partition coefficient (log P) of flavonoids; however, their toxicity to HL‐60 cells was described by equation log cL50 (μM) = 3.0161 + 1.1099 Ep/2 (V) — 0.3369 log P. The toxicity of quercetin was partly prevented by nontoxic concentrations of other flavonoids examined, thus pointing out to potential neutralization of quercetin cytotoxicity by intake of flavonoid mixtures.

Incubation of HL‐60 cells with anthracycline daunorubicin caused an appearance of viable apoptotic, nonviable apoptotic, necrotic (nonviable nonapoptotic) and chromatin‐free (late apoptotic) cells. Both necrotic and apoptotic cell responses were partly prevented by antioxidant N,N′‐diphenyl‐p‐phenylene diamine (DPPD) and iron‐chelating agent, desferrioxamine, suggesting an involvement of activated oxygen species. The comparison of cytotoxicity of daunorubicin and of 5‐hydroxy‐ and 5,8‐dihydroxy‐1,4‐naphthoquinones revealed that at equitoxic concentrations, hydroxynaphthoquinones induced a larger number of necrotic cells in comparison to daunorubicin, a process being partly prevented by DPPD and desferrioxamine. However, we have found that cytotoxicity of daunorubicin was markedly higher in comparison with a series of naphtho‐ and benzoquinones, where an increase of cytotoxicity upon increase in single‐electron reduction potential of quinones (E17) was observed, pointing out to redox cycling as to the main factor of cytotoxicity. This discrepancy could be explained by additional factor(s) of daunorubicin cytotoxicity, e.g. DNA‐intercalation, or selective accumulation of daunorubicin in cell nucleus.

Bovine leukemia virus-transformed lamb embryo fibroblasts (line FLK) possess activity of DT-diaphorase of ca. 260 U/mg protein and similar levels of other NADP(H)-oxidizing enzymes: NADH:oxidase, 359 U/mg; NADPH:oxidase, 43 U/mg; NADH:cytochrome-c reductase, 141 U/mg; NADPH:cytochrome-c reductase, 43 U/mg. In general, the toxicity of aromatic nitrocompounds towards FLK cells increases on increase of single-electron reduction potentials (E1(1)) of nitrocompounds or the log of their reduction rate constants by single-electron-transferring enzymes, microsomal NADPH:cytochrome P-450 reductase (EC 1.6.2.4) and mitochondrial NADH:ubiquinone reductase (EC 1.6.99.3). No correlation between the toxicity and reduction rate of nitrocompounds by rat liver DT-diaphorase (EC 1.6.99.2) was observed. The toxicity is not significantly affected by dicumarol, an inhibitor of DT-diaphorase. Nitrocompounds examined were poor substrates for DT-diaphorase, being 10(4) times less active than menadione. Their poor reactivity is most probably determined by their preferential binding to a NADPH binding site, but not to menadione binding site of diaphorase. These data indicate that at comparable activities of DT-diaphorase and single-electron-transferring NAD(P)H dehydrogenases in the cell, the toxicity of nitrocompounds will be determined mainly by their single-electron reduction reactions.