title: The reactivity of o-quinones which do not isomerize to quinone methides correlates with alkylcatechol-induced toxicity in human melanoma cells.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago 60612-7231, USA. Judy.Bolton@UIC.edu
authors.forename: J L
authors.initials: JL
authors.lastname: Bolton
authors.forename: E
authors.initials: E
authors.lastname: Pisha
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: E S
authors.initials: ES
authors.lastname: Krol
authors.forename: S L
authors.initials: SL
authors.lastname: Iverson
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: R B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: J M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D001711:Biotransformation; D002396:Catechols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008956:Models, Chemical; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D011809:Quinones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D002396:Catechols; D011809:Quinones; D010088:Oxidoreductases; D014442:Monophenol Monooxygenase; D005978:Glutathione