THE REACTIVITY OF O-QUINONES WHICH DO NOT ISOMERIZE TO QUINONE METHIDES CORRELATES WITH ALKYLCATECHOL-INDUCED TOXICITY IN HUMAN-MELANOMA CELLS

Catechols are widespread in the environment, especially as constituent s of edible plants. A number of these catechols may undergo oxidative metabolism to electrophilic o-quinones (3,5-cyclohexadien-1,2-dione) b y oxidative enzymes such as cytochrome P450 and peroxidases. Alkylatio n of cellular nucleophiles by these intermediates and the formation of reactive oxygen species, especially through redox cycling of o-quinon es, could contribute to the cytotoxic properties of the parent catecho ls. In contrast, isomerization of the o-quinones to electrophilic quin one methides (4-methylene-2,5-cyclohexadien-1-one, QM) could cause cel lular damage primarily through alkylation. In this investigation, we t reated human melanoma cells with two groups of catechols. These cells have high levels of tyrosinase required to oxidize catechols to quinoi ds. For catechols which are oxidized to o-quinones that cannot isomeri ze 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, c atechols which are metabolized by the o-quinone/p-quinone methide bioa ctivation pathway were equally cytotoxic but showed no correlation bet ween 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 th e o-quinone/QM pathway in catechol toxicity depends on a combination b etween the rate of enzymatic formation of the o-quinone, the rate of i somerization to the more electrophilic QM, and the chemical reactivity of the quinoids. (C) 1997 Elsevier Science Ireland Ltd.