Catechols are widespread in the environment, especially as constituents of edible plants. A number of these
catechols may undergo oxidative metabolism to electrophilic o-
quinones (3,5-cyclohexadien-1,2-dione) by oxidative
enzymes such as
cytochrome P450 and
peroxidases. Alkylation of cellular nucleophiles by these intermediates and the formation of
reactive oxygen species, especially through redox cycling of o-
quinones, could contribute to the cytotoxic properties of the parent
catechols. In contrast, isomerization of the o-
quinones to electrophilic
quinone methides (4-methylene-2,5-cyclohexadien-1-one, QM) could cause cellular damage primarily through alkylation. In this investigation, we treated human
melanoma cells with two groups of
catechols. These cells have high levels of
tyrosinase required to oxidize
catechols to quinoids. For
catechols which are oxidized to o-
quinones that cannot isomerize to
quinone methides or form unstable
quinone methides, plots of the cytotoxicity data (ED50) versus the reactivity of the o-
quinones gave an excellent linear correlation; decreasing o-
quinone reactivity led to a decrease in the cytotoxic potency of the
catechol. In contrast,
catechols which are metabolized by the o-
quinone/p-
quinone methide bioactivation pathway were equally cytotoxic but showed no correlation between the reactivity of the o-
quinones and the cytotoxic potency of the
catechols. The most likely explanation for this effect is a change in cytotoxic mechanism from o-
quinone-mediated inhibition of cell growth to a bioactivation pathway based on both o-
quinone and p-QM formation. These results substantiate the conclusion that the involvement of the o-
quinone/ QM pathway in
catechol toxicity depends on a combination between the rate of enzymatic formation of the o-
quinone, the rate of isomerization to the more electrophilic QM, and the chemical reactivity of the quinoids.