Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone.

Implications for mutagenic activity

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E 2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3′,4′-quinone (HES-3′, 4′-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E 2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E 2-3,4-Q or HES-3′,4′-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE 2-1-N7Gua and 3′-OH-HES-6′-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations.

Original languageEnglish (US)
Pages (from-to)29-35
Number of pages7
JournalSteroids
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Hexestrol
Deoxyribose
Catechol Estrogens
Estradiol Congeners
Quinones
DNA
Guanine
Adenine
Half-Life
Estrogens
Non-Steroidal Estrogens
Mutation
Estrone
Carcinogens
Tumors
Estradiol
Repair
Oxidation
benzoquinone
estradiol-3,4-quinone

Keywords

  • 1,4-Michael addition
  • Catechol quinones
  • Depurinating DNA adducts
  • Steroidal and nonsteroidal estrogens

ASJC Scopus subject areas

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

Cite this

@article{3a197f8e8c424fa2972bdb00a631c65d,
title = "Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone.: Implications for mutagenic activity",
abstract = "A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E 2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3′,4′-quinone (HES-3′, 4′-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E 2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E 2-3,4-Q or HES-3′,4′-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE 2-1-N7Gua and 3′-OH-HES-6′-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations.",
keywords = "1,4-Michael addition, Catechol quinones, Depurinating DNA adducts, Steroidal and nonsteroidal estrogens",
author = "Muhammad Saeed and Muhammad Zahid and Gunselman, {Sandra J.} and Rogan, {Eleanor G} and Ercole Cavalieri",
year = "2005",
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T1 - Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3′,4′-quinone.

T2 - Implications for mutagenic activity

AU - Saeed, Muhammad

AU - Zahid, Muhammad

AU - Gunselman, Sandra J.

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

PY - 2005/1/1

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N2 - A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E 2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3′,4′-quinone (HES-3′, 4′-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E 2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E 2-3,4-Q or HES-3′,4′-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE 2-1-N7Gua and 3′-OH-HES-6′-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations.

AB - A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E 2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3′,4′-quinone (HES-3′, 4′-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E 2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E 2-3,4-Q or HES-3′,4′-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE 2-1-N7Gua and 3′-OH-HES-6′-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations.

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KW - Steroidal and nonsteroidal estrogens

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