Balance of beneficial and deleterious health effects of quinones: A case study of the chemical properties of genistein and estrone quinones

Qiang Zhang, Tingting Tu, D. Andréa D'Avignon, Michael L. Gross

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Substances containing a phenolic moiety are often metabolized to quinones whose high reactivity makes them difficult to study. Some of these precursors have clear health benefits, and some quinones themselves are used in cancer therapy, whereas others are deleterious. For example, dietary intake of phytoestrogen, genistein (Gen), seems to play a preventive role in breast cancer (BC) whereas prolonged exposure to chemically similar mammalian estrogens is clearly associated with elevated incidence of BC. Although both can be metabolized to reactive quinones, the catechol estrogen quinones (CEQs) modify DNA by redox cycling and/or depurination via a Michael addition. Here, we report an investigation of the chemical reactivity of Gen and estrone quinones to determine the chemical differences of these two biologically important molecules. The catechol genistein quinone (CGenQ), has a half-life of 4 ± 1s under physiological condition, as determined by glutathione trapping. It disappears by reacting with H2O to give a dihydrate, CGenQ• (H 2O) 2, whose structure was proved by NMR. Under reductive conditions, CGenQ• (H 2O) 2 is readily reduced to reform the catechol genistein (CGen). This reversible oxidation of CGen to CGenQ and the prompt moderation of its reactivity by hydration to CGenQ •(H 2O) 2 effectively hinders any redox cycling or depurination reaction of CGenQ with DNA. Catechol estrogen quinones, on the other hand, are sufficiently long-lived that they can damage DNA via a Michael addition or by redox cycling. Although the reactivity of CEQ in a nonaqueous solvent is similar to that of CGenQ, its reactivity in aqueous media with the free Ade base is more than 600 times that of CGenQ. These results suggest that rapid hydration of a quinone can moderate its reactivity toward biomolecules, allowing them to express, for example, estrogen-like properties without exhibiting the deleterious properties of redox cycling or directly damaging DNA via depurination reactions.

Original languageEnglish (US)
Pages (from-to)1067-1076
Number of pages10
JournalJournal of the American Chemical Society
Issue number3
StatePublished - Jan 28 2009
Externally publishedYes


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