Histone nuclear proteins are irreversibly modified by reactive metabolites of diethylstilbestrol Article

Roy, D, Pathak, DN. (1995). Histone nuclear proteins are irreversibly modified by reactive metabolites of diethylstilbestrol . Journal of Toxicology and Environmental Health - Part A, 44(4), 449-459. 10.1080/15287399509531973

cited authors

  • Roy, D; Pathak, DN

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. Cel electrophoresis experiments revealed that all five histones, 1, 2A, 2B, 3, and 4, were irreversibly bound to 13H]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 µM and 750 pmol/mg protein/30 min, respectively. This binding was significantly inhibited by cytochromes P-450 inhibitors. Low-molecular-weight thiols, such as glu-tathione 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 his-tone-binding metabolites, presumably by nuclear cytochromes 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. © 1975 Taylor & Francis Group, LLC.

authors

publication date

  • January 1, 1995

published in

Digital Object Identifier (DOI)

start page

  • 449

end page

  • 459

volume

  • 44

issue

  • 4