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This review summarises current knowledge on the various molecular chemopreventive or therapeutic mechanisms that may be involved when the administration of flavonoids or polyphenols prevented chemical carcinogenesis in animal models. These mechanisms can be subdivided into the following: 1) the molecular mechanisms involved in preventing carcinogen metabolic activation, 2) the molecular mechanisms for preventing tumour cell proliferation by inactivation or downregulation of prooxidant enzymes or signal transduction enzymes, 3) the molecular cell death mechanisms for the induction of tumour cell death (apoptosis) and the molecular mechanisms for the inhibition of isolated mitochondria functions. Many of the flavonoids and polyphenols found in diets, supplements or herbal medicine were also ranked using "accelerated cytotoxic mechanism screening" by a combinatorial approach utilising isolated rat hepatocytes. A strong correlation of an early collapse of the mitochondrial membrane potential and cell death was found for most of the cytotoxic polyphenols but did not occur with non-toxic polyphenols. This screening could prove useful for eliminating polyphenols that have the potential for adverse health effects and for selecting safe and effective polyphenolic candidates for further development as supplements for preventing cancer or cardiovascular disease. Safety concerns of flavonoid/polyphenol supplements are also reviewed.

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The metabolic pathways of dietary flavonoids are still largely unknown. In the present work, mass spectrometry and UV-vis spectroscopy studies were used to show that the naturally occurring flavonoid catechin underwent enzymatic oxidation by tyrosinase in the presence of glutathione (GSH) to form mono-, bi-, and tri-glutathione conjugates of catechin and mono- and bi-glutathione conjugates of a catechin dimer. A hydroxylated catechin adduct was also detected. Using UV spectroscopy, it was shown that the catechol B-ring of catechin was oxidized by tyrosinase to form an o-quinone which could be reduced back to catechin with potassium borohydride or reacted with GSH to form glutathione conjugates. The catechin-glutathione conjugates formed had much lower distribution coefficient values than catechin itself. When peroxidase and hydrogen peroxide were used instead of tyrosinase, only mono-glutathione conjugates were formed but not bi-glutathione conjugates or hydroxylated adducts. (1)H NMR evidence showed that three different mono-glutathione conjugates on ring B of catechin were formed by peroxidase and hydrogen peroxide. Rat liver microsomes and NADPH or cumene hydroperoxide also catalyzed catechin-glutathione conjugate formation which was prevented by benzylimidazole, a P450 2E1 inhibitor. Catechin cytotoxicity toward isolated hepatocytes was also markedly enhanced by hydrogen peroxide or cumene hydroperoxide and was prevented by benzylimidazole, suggesting that catechin could be metabolically activated by P450 peroxidase activity to form cytotoxic quinoid species.

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In this work, we investigated the biochemical mechanism of acetaminophen (APAP) induced toxicity in SK-MEL-28 melanoma cells using tyrosinase enzyme as a molecular cancer therapeutic target. Our results showed that APAP was metabolized 87% by tyrosinase at 2h incubation. AA and NADH, quinone reducing agents, were significantly depleted during APAP oxidation by tyrosinase. The IC 50 (48h) of APAP towards SK-MEL-28, MeWo, SK-MEL-5, B16-F0 and B16-F10 melanoma cells was 100μM whereas it showed no significant toxicity towards BJ, Saos-2, SW-620, and PC-3 non-melanoma cells, demonstrating selective toxicity towards melanoma cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, enhanced APAP toxicity towards SK-MEL-28 cells. AA and GSH were effective in preventing APAP induced melanoma cell toxicity. Trifluoperazine and cyclosporin A, inhibitors of permeability transition pore in mitochondria, significantly prevented APAP melanoma cell toxicity. APAP caused time and dose-dependent decline in intracellular GSH content in SK-MEL-28, which preceded cell toxicity. APAP led to ROS formation in SK-MEL-28 cells which was exacerbated by dicoumarol and 1-bromoheptane whereas cyslosporin A and trifluoperazine prevented it. Our investigation suggests that APAP is a tyrosinase substrate, and that intracellular GSH depletion, ROS formation and induced mitochondrial toxicity contributed towards APAP's selective toxicity in SK-MEL-28 cells.