Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol

The defining link to natural estrogens

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Abstract

Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3'-hydroxyDES (3'-OH-DES) which can further oxidize to DES-3',4'-quinone (DES-3',4'-Q). Similarly to estradiol-3,4-qui-none, the reaction of DES-3',4'-Q with DNA would form the depu-rinating 3'-OH-DES-6'-N3Ade and 3-OH-DES-6-N7Gua adducts. To prove this hypothesis, synthesis of DES-3',4'-Q bv oxidation of 3'-OH-DES with Ag 2O was tried; this failed doe to instantaneous formation of a spiro-quinone. Oxidation of 3'-OH-DES by lacto-peroxidase or tyrosinase in the presence of DNA led to the formation of 3-OH-DES-6'-3Ade and 3-OH-DES-6'-N7Gua adducts. These adducts were tentatively identified bv LC- MS MS as 3 -OH-DES-6'-N3Ade, mlz = 418 [M+H] +, and 3'-OH-DES-6'-N7Gua, mlz = 434 [M+H| =. Demonstration of their structures derived from their oxidation by MnO 2 to the DES quinone adducts and subsequent tautomerization to the dienestrol (DIES) catechol adducts, which are identical to the standard 3' -OH-DIES-6' -N3Ade, mlz = 416 [M+H] +, and 3'-OH-DIES-6'-N7Gua, mlz =432 [M + H] +, adducts. The reaction of DIES-3/ .4' -Q or lactoper-oxidase-aetivated 3' -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3' -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol qui nones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.

Original languageEnglish (US)
Pages (from-to)1276-1284
Number of pages9
JournalInternational Journal of Cancer
Volume124
Issue number6
DOIs
StatePublished - Mar 15 2009

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Diethylstilbestrol
DNA Adducts
Carcinogens
Estrogens
Dienestrol
DNA
Metabolic Activation
hydroxide ion
Estradiol
Estradiol Congeners
Monophenol Monooxygenase

Keywords

  • DES catechol quinone
  • Depurinating DES-DNA adducts
  • Metabolic activation of DES

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{9013fd31d9eb4607aba9bd676a8f4040,
title = "Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens",
abstract = "Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3'-hydroxyDES (3'-OH-DES) which can further oxidize to DES-3',4'-quinone (DES-3',4'-Q). Similarly to estradiol-3,4-qui-none, the reaction of DES-3',4'-Q with DNA would form the depu-rinating 3'-OH-DES-6'-N3Ade and 3-OH-DES-6-N7Gua adducts. To prove this hypothesis, synthesis of DES-3',4'-Q bv oxidation of 3'-OH-DES with Ag 2O was tried; this failed doe to instantaneous formation of a spiro-quinone. Oxidation of 3'-OH-DES by lacto-peroxidase or tyrosinase in the presence of DNA led to the formation of 3-OH-DES-6'-3Ade and 3-OH-DES-6'-N7Gua adducts. These adducts were tentatively identified bv LC- MS MS as 3 -OH-DES-6'-N3Ade, mlz = 418 [M+H] +, and 3'-OH-DES-6'-N7Gua, mlz = 434 [M+H| =. Demonstration of their structures derived from their oxidation by MnO 2 to the DES quinone adducts and subsequent tautomerization to the dienestrol (DIES) catechol adducts, which are identical to the standard 3' -OH-DIES-6' -N3Ade, mlz = 416 [M+H] +, and 3'-OH-DIES-6'-N7Gua, mlz =432 [M + H] +, adducts. The reaction of DIES-3/ .4' -Q or lactoper-oxidase-aetivated 3' -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3' -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol qui nones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.",
keywords = "DES catechol quinone, Depurinating DES-DNA adducts, Metabolic activation of DES",
author = "Muhammad Saeed and Rogan, {Eleanor G} and Ercole Cavalieri",
year = "2009",
month = "3",
day = "15",
doi = "10.1002/ijc.24113",
language = "English (US)",
volume = "124",
pages = "1276--1284",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

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TY - JOUR

T1 - Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol

T2 - The defining link to natural estrogens

AU - Saeed, Muhammad

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

PY - 2009/3/15

Y1 - 2009/3/15

N2 - Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3'-hydroxyDES (3'-OH-DES) which can further oxidize to DES-3',4'-quinone (DES-3',4'-Q). Similarly to estradiol-3,4-qui-none, the reaction of DES-3',4'-Q with DNA would form the depu-rinating 3'-OH-DES-6'-N3Ade and 3-OH-DES-6-N7Gua adducts. To prove this hypothesis, synthesis of DES-3',4'-Q bv oxidation of 3'-OH-DES with Ag 2O was tried; this failed doe to instantaneous formation of a spiro-quinone. Oxidation of 3'-OH-DES by lacto-peroxidase or tyrosinase in the presence of DNA led to the formation of 3-OH-DES-6'-3Ade and 3-OH-DES-6'-N7Gua adducts. These adducts were tentatively identified bv LC- MS MS as 3 -OH-DES-6'-N3Ade, mlz = 418 [M+H] +, and 3'-OH-DES-6'-N7Gua, mlz = 434 [M+H| =. Demonstration of their structures derived from their oxidation by MnO 2 to the DES quinone adducts and subsequent tautomerization to the dienestrol (DIES) catechol adducts, which are identical to the standard 3' -OH-DIES-6' -N3Ade, mlz = 416 [M+H] +, and 3'-OH-DIES-6'-N7Gua, mlz =432 [M + H] +, adducts. The reaction of DIES-3/ .4' -Q or lactoper-oxidase-aetivated 3' -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3' -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol qui nones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.

AB - Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3'-hydroxyDES (3'-OH-DES) which can further oxidize to DES-3',4'-quinone (DES-3',4'-Q). Similarly to estradiol-3,4-qui-none, the reaction of DES-3',4'-Q with DNA would form the depu-rinating 3'-OH-DES-6'-N3Ade and 3-OH-DES-6-N7Gua adducts. To prove this hypothesis, synthesis of DES-3',4'-Q bv oxidation of 3'-OH-DES with Ag 2O was tried; this failed doe to instantaneous formation of a spiro-quinone. Oxidation of 3'-OH-DES by lacto-peroxidase or tyrosinase in the presence of DNA led to the formation of 3-OH-DES-6'-3Ade and 3-OH-DES-6'-N7Gua adducts. These adducts were tentatively identified bv LC- MS MS as 3 -OH-DES-6'-N3Ade, mlz = 418 [M+H] +, and 3'-OH-DES-6'-N7Gua, mlz = 434 [M+H| =. Demonstration of their structures derived from their oxidation by MnO 2 to the DES quinone adducts and subsequent tautomerization to the dienestrol (DIES) catechol adducts, which are identical to the standard 3' -OH-DIES-6' -N3Ade, mlz = 416 [M+H] +, and 3'-OH-DIES-6'-N7Gua, mlz =432 [M + H] +, adducts. The reaction of DIES-3/ .4' -Q or lactoper-oxidase-aetivated 3' -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3' -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol qui nones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts.

KW - DES catechol quinone

KW - Depurinating DES-DNA adducts

KW - Metabolic activation of DES

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