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

ABSTRACT: 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 +/- 1 s under physiological condition, as determined by glutathione trapping. It disappears by reacting with H2O to give a dihydrate, CGenQ x (H2O)2, whose structure was proved by NMR. Under reductive conditions, CGenQ x (H2O)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 x (H2O)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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC2631626 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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

Zhang Qiang Q Tu Tingting T d'Avignon D André DA Gross Michael L ML

Journal of the American Chemical Society 20090101 3

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 ...[more]

PMID: 19115854

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Project description:Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when [Formula: see text] where U is deleterious mutation rate and [Formula: see text] is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by [Formula: see text] We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by [Formula: see text] where [Formula: see text] is mean selective advantage of beneficial mutations, and [Formula: see text] This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut down the adaptive process. We derive critical mutation rates above which these two events become likely.

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

Publications

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

Similar Datasets

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