Cytotoxicity of natural hydroxyanthraquinones: role of oxidative stress.

In order to assess the role of oxidative stress in the cytotoxicity of natural hydroxyanthraquinones, we compared rhein, emodin, danthron, chrysophanol, and carminic acid, and a series of model quinones with available values of single-electron reduction midpoint potential at pH 7.0 (E(1)7), with respect to their reactivity in the single-electron enzymatic reduction, and their mammalian cell toxicity. The toxicity of model quinones to the bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK), and HL-60, a human promyelocytic leukemia cell line, increased with an increase in their E(1)7. A close parallelism was found between the reactivity of hydroxyanthraquinones and model quinones with single-electron transferring flavoenzymes ferredoxin: NADP+ reductase and NADPH:cytochrome P450 reductase, and their cytotoxicity. This points to the importance of oxidative stress in the toxicity of hydroxyanthraquinones in these cell lines, which was further evidenced by the protective effects of desferrioxamine and the antioxidant N,N'-diphenyl-p-phenylene diamine, by the potentiating effects of 1,3-bis-(2-chloroethyl)-1-nitrosourea, and an increase in lipid peroxidation.

Quantitative structure-activity relationships in prooxidant cytotoxicity of polyphenols: role of potential of phenoxyl radical/phenol redox couple.

The aim of this work was to characterize the role of the potential of phenoxyl radical/phenol redox couple, E(7)(2), in the cytotoxicity of polyphenols. The cytotoxicity of polyphenols in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK), and human promyelocytic leukemia cells (line HL-60) was partly inhibited by catalase, by the antioxidant N,N'-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis-(2-chloro-ethyl)-1-nitrosourea, thus showing its prooxidant character. Dapsone, an inhibitor of myeloperoxidase, did not affect the cytotoxicity of polyphenols in HL-60 cells, whereas dicumarol, an inhibitor of DT-diaphorase, showed controversial effects on their cytotoxicity in FLK cells. Inhibitors of cytochromes P-450, alpha-naphthoflavone and izoniazide, decreased the cytotoxicity of several polyphenols, whereas 3,5-dinitrocatechol, an inhibitor of catechol-o-methyltransferase (COMT), increased it. The cytotoxicity of 13 polyhydroxybenzenes was described by the equations: logcL50 (microM) = -0.67 + 5.46E(7)(2) (V) - 0.16 logD (FLK), and logcL50 (microM) = -1.39 + 6.90E(7)(2) (V) - 0.20logD (HL-60), where cL50 is compound concentration for 50% cell survival, and D is octanol/water distribution coefficient at pH 7.0. The flavonoids comprise a separate series of compounds with lower cytotoxicity. The correlations obtained quantitatively confirm the parallelism between the polyphenol cytotoxicity and the rates of their single-electron oxidation, and point to the leading role of formation of the reactive oxygen species in their cytotoxicity. Depending on the examined system, this parallelism may be distorted due to the cytochrome P-450 and COMT-catalyzed transformation of polyphenols.