Molecular effects and gene function influence in ref to developmental exposure to DES
1995 Study Abstract
We demonstrate for the first time that diethylstilbestrol (DES), a synthetic estrogen, is converted by nuclei to histone-binding metabolite(s).
Reaction of [3H]DES with nuclei in the presence of cumene hydroperoxide or NADPH revealed binding of [3H]DES to histone nuclear proteins. Gel electrophoresis experiments revealed that all five histones, 1, 2A, 2B, 3, and 4, were irreversibly bound to [3H]DES. Histones 1 and 3 were more susceptible to the attack by [3H]DES quinone, a metabolite of DES, than histones 2A, 2B, or 4. The kinetic constants, Km and Vmax, of this binding reaction in the presence of cumene hydroperoxide were 10 microM and 750 pmol/mg protein/30 min, respectively. This binding was significantly inhibited by cytochromes P-450 inhibitors. Low-molecular-weight thiols, such as glutathione and cysteine, or thiol modifiers, such as n-ethylmaleimide, dithionitrobenzoic acid, and hydroxymercuric benzoate, drastically inhibited binding of [3H]DES quinone to histone 3. The binding of [3H]DES metabolites to both transcriptionally active and inactive chromatin histone proteins was observed.
We conclude that DES is metabolized to histone-binding metabolites, presumably by nuclear cytochrome P-450. DES quinone may be one of the histone-binding DES metabolites.
These data suggest that an analogous in vivo modification in the transcriptionally active chromatin histones by DES metabolites may influence gene function.
- Histone nuclear proteins are irreversibly modified by reactive metabolites of diethylstilbestrol, Journal of toxicology and environmental health, NCBI PubMed PMID : 7723077, 1995 Apr.
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