Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′-hydroxyhexestrol: Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens

Muhammad Saeed, Sandra J. Gunselman, Sheila Higginbotham, Eleanor G Rogan, Ercole Cavalieri

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Abstract

The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3-C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412-9.]. We report here formation of the depurinating adduct 3′-OH-HES-6′-N3Ade by reaction of HES-3′,4′-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (<1%) levels of unidentified stable adducts were detected in the DNA from these reactions. These results are similar to those obtained by reaction of endogenous catechol estrogen-3,4-quinones with DNA. The similarities extend to the instantaneously-depurinating N3Ade adducts and relatively slowly-depurinating N7Gua adducts. The endogenous estrogens, estrone and estradiol, their 4-catechol estrogens and HES are carcinogenic in the kidney of Syrian golden hamsters. These results suggest that estrone (estradiol)-3,4- quinones and HES-3′,4′-Q are the ultimate carcinogenic metabolites of the natural and synthetic estrogens, respectively. Reaction of the electrophilic quinones by 1,4-Michael addition with DNA at the nucleophilic N-3 of Ade and N-7 of Gua is suggested to be the major critical step in tumor initiation by these compounds.

Original languageEnglish (US)
Pages (from-to)37-45
Number of pages9
JournalSteroids
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Hexestrol
Estradiol Congeners
DNA Adducts
Tumors
DNA
Enzymes
Neoplasms
Non-Steroidal Estrogens
Metabolites
Estrone
3'-hydroxyhexestrol
benzoquinone
Estrogens
Chemical activation
Catechol Estrogens
Lactoperoxidase
Quinones

Keywords

  • Catechol quinones
  • Depurinating N3adenine adduct
  • Depurinating N7guanine adduct
  • Nonsteroidal synthetic estrogen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

@article{20ed779289694d8daa4ac507793a92a7,
title = "Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′-hydroxyhexestrol: Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens",
abstract = "The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3-C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412-9.]. We report here formation of the depurinating adduct 3′-OH-HES-6′-N3Ade by reaction of HES-3′,4′-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (<1{\%}) levels of unidentified stable adducts were detected in the DNA from these reactions. These results are similar to those obtained by reaction of endogenous catechol estrogen-3,4-quinones with DNA. The similarities extend to the instantaneously-depurinating N3Ade adducts and relatively slowly-depurinating N7Gua adducts. The endogenous estrogens, estrone and estradiol, their 4-catechol estrogens and HES are carcinogenic in the kidney of Syrian golden hamsters. These results suggest that estrone (estradiol)-3,4- quinones and HES-3′,4′-Q are the ultimate carcinogenic metabolites of the natural and synthetic estrogens, respectively. Reaction of the electrophilic quinones by 1,4-Michael addition with DNA at the nucleophilic N-3 of Ade and N-7 of Gua is suggested to be the major critical step in tumor initiation by these compounds.",
keywords = "Catechol quinones, Depurinating N3adenine adduct, Depurinating N7guanine adduct, Nonsteroidal synthetic estrogen",
author = "Muhammad Saeed and Gunselman, {Sandra J.} and Sheila Higginbotham and Rogan, {Eleanor G} and Ercole Cavalieri",
year = "2005",
month = "1",
day = "1",
doi = "10.1016/j.steroids.2004.09.012",
language = "English (US)",
volume = "70",
pages = "37--45",
journal = "Steroids",
issn = "0039-128X",
publisher = "Elsevier Inc.",
number = "1",

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TY - JOUR

T1 - Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3′,4′-quinone or enzyme-activated 3′-hydroxyhexestrol

T2 - Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens

AU - Saeed, Muhammad

AU - Gunselman, Sandra J.

AU - Higginbotham, Sheila

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

PY - 2005/1/1

Y1 - 2005/1/1

N2 - The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3-C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412-9.]. We report here formation of the depurinating adduct 3′-OH-HES-6′-N3Ade by reaction of HES-3′,4′-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (<1%) levels of unidentified stable adducts were detected in the DNA from these reactions. These results are similar to those obtained by reaction of endogenous catechol estrogen-3,4-quinones with DNA. The similarities extend to the instantaneously-depurinating N3Ade adducts and relatively slowly-depurinating N7Gua adducts. The endogenous estrogens, estrone and estradiol, their 4-catechol estrogens and HES are carcinogenic in the kidney of Syrian golden hamsters. These results suggest that estrone (estradiol)-3,4- quinones and HES-3′,4′-Q are the ultimate carcinogenic metabolites of the natural and synthetic estrogens, respectively. Reaction of the electrophilic quinones by 1,4-Michael addition with DNA at the nucleophilic N-3 of Ade and N-7 of Gua is suggested to be the major critical step in tumor initiation by these compounds.

AB - The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3-C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3′-OH-HES, which can be metabolically converted to the catechol quinone, HES-3′,4′-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3′,4′-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3′-OH-HES-6′-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412-9.]. We report here formation of the depurinating adduct 3′-OH-HES-6′-N3Ade by reaction of HES-3′,4′-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3′-OH-HES-6′-N7Gua and 3′-OH-HES-6′-N3Ade adducts by reaction of HES-3′,4′-Q with DNA or by activation of 3′-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (<1%) levels of unidentified stable adducts were detected in the DNA from these reactions. These results are similar to those obtained by reaction of endogenous catechol estrogen-3,4-quinones with DNA. The similarities extend to the instantaneously-depurinating N3Ade adducts and relatively slowly-depurinating N7Gua adducts. The endogenous estrogens, estrone and estradiol, their 4-catechol estrogens and HES are carcinogenic in the kidney of Syrian golden hamsters. These results suggest that estrone (estradiol)-3,4- quinones and HES-3′,4′-Q are the ultimate carcinogenic metabolites of the natural and synthetic estrogens, respectively. Reaction of the electrophilic quinones by 1,4-Michael addition with DNA at the nucleophilic N-3 of Ade and N-7 of Gua is suggested to be the major critical step in tumor initiation by these compounds.

KW - Catechol quinones

KW - Depurinating N3adenine adduct

KW - Depurinating N7guanine adduct

KW - Nonsteroidal synthetic estrogen

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