Thiols can either enhance or suppress DNA damage induction by catecholestrogens

Paul A. Thibodeau, Suzanne Kocsis-Bédard, Josiane Courteau, Théophile Niyonsenga, Benoit Paquette

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involved in carcinogenesis and the development of resistance to methotrexate. This induction of drug resistance correlates with the relative efficiency of catecholestrogens in the generation of reactive oxygen species (ROS) and the induction of DNA strand breaks. Although antioxidants can neutralize ROS, the generation of these reactive species by catecholestrogens can be enhanced by electron donors like NADH. Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H2O2 generating system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential. In contrast, the GSH precursor NAC at low concentrations was able to enhance the level of oxidative damage, as observed with NADH. NAC can reduce Cu(II) to Cu(I) producing the radical NAC·, which can generate the superoxide anion. However, the importance of this pathway appears to be relatively minor since the addition of NAC to the 4-hydroxyestradiol/Cu(II) system generates about 15 times more DNA strand breaks than NAC and Cu(II) alone. We suggest that NAC can perpetuate the redox cycle between the quinone and the semiquinone forms of the catecholestrogens, thereby enhancing the production of ROS. In conclusion, this study demonstrates the crucial importance of the choice of antioxidant as potential therapy against the negative biological effects of estrogens.

Original languageEnglish
Pages (from-to)62-73
Number of pages12
JournalFree Radical Biology and Medicine
Volume30
Issue number1
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Catechol Estrogens
Sulfhydryl Compounds
DNA Damage
8,11,14-Eicosatrienoic Acid
Reactive Oxygen Species
DNA Breaks
DNA
NAD
Estrogens
Antioxidants
Metabolites
Drug Resistance
Methotrexate
Superoxides
Oxidation-Reduction
Carcinogenesis
Electrons
Pharmaceutical Preparations
4-hydroxyestradiol

Cite this

Thibodeau, Paul A. ; Kocsis-Bédard, Suzanne ; Courteau, Josiane ; Niyonsenga, Théophile ; Paquette, Benoit. / Thiols can either enhance or suppress DNA damage induction by catecholestrogens. In: Free Radical Biology and Medicine. 2001 ; Vol. 30, No. 1. pp. 62-73.
@article{1b184612efca4df1a24b8099f24dde15,
title = "Thiols can either enhance or suppress DNA damage induction by catecholestrogens",
abstract = "The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involved in carcinogenesis and the development of resistance to methotrexate. This induction of drug resistance correlates with the relative efficiency of catecholestrogens in the generation of reactive oxygen species (ROS) and the induction of DNA strand breaks. Although antioxidants can neutralize ROS, the generation of these reactive species by catecholestrogens can be enhanced by electron donors like NADH. Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H2O2 generating system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential. In contrast, the GSH precursor NAC at low concentrations was able to enhance the level of oxidative damage, as observed with NADH. NAC can reduce Cu(II) to Cu(I) producing the radical NAC·, which can generate the superoxide anion. However, the importance of this pathway appears to be relatively minor since the addition of NAC to the 4-hydroxyestradiol/Cu(II) system generates about 15 times more DNA strand breaks than NAC and Cu(II) alone. We suggest that NAC can perpetuate the redox cycle between the quinone and the semiquinone forms of the catecholestrogens, thereby enhancing the production of ROS. In conclusion, this study demonstrates the crucial importance of the choice of antioxidant as potential therapy against the negative biological effects of estrogens.",
keywords = "Antioxidants, Breast cancer, Catecholestrogen, Free radicals, Glutathione, Hydroxyestrogen, N-acetylcysteine",
author = "Thibodeau, {Paul A.} and Suzanne Kocsis-B{\'e}dard and Josiane Courteau and Th{\'e}ophile Niyonsenga and Benoit Paquette",
year = "2001",
doi = "10.1016/S0891-5849(00)00446-9",
language = "English",
volume = "30",
pages = "62--73",
journal = "Free Radical Biology Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "1",

}

Thiols can either enhance or suppress DNA damage induction by catecholestrogens. / Thibodeau, Paul A.; Kocsis-Bédard, Suzanne; Courteau, Josiane; Niyonsenga, Théophile; Paquette, Benoit.

In: Free Radical Biology and Medicine, Vol. 30, No. 1, 2001, p. 62-73.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Thiols can either enhance or suppress DNA damage induction by catecholestrogens

AU - Thibodeau, Paul A.

AU - Kocsis-Bédard, Suzanne

AU - Courteau, Josiane

AU - Niyonsenga, Théophile

AU - Paquette, Benoit

PY - 2001

Y1 - 2001

N2 - The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involved in carcinogenesis and the development of resistance to methotrexate. This induction of drug resistance correlates with the relative efficiency of catecholestrogens in the generation of reactive oxygen species (ROS) and the induction of DNA strand breaks. Although antioxidants can neutralize ROS, the generation of these reactive species by catecholestrogens can be enhanced by electron donors like NADH. Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H2O2 generating system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential. In contrast, the GSH precursor NAC at low concentrations was able to enhance the level of oxidative damage, as observed with NADH. NAC can reduce Cu(II) to Cu(I) producing the radical NAC·, which can generate the superoxide anion. However, the importance of this pathway appears to be relatively minor since the addition of NAC to the 4-hydroxyestradiol/Cu(II) system generates about 15 times more DNA strand breaks than NAC and Cu(II) alone. We suggest that NAC can perpetuate the redox cycle between the quinone and the semiquinone forms of the catecholestrogens, thereby enhancing the production of ROS. In conclusion, this study demonstrates the crucial importance of the choice of antioxidant as potential therapy against the negative biological effects of estrogens.

AB - The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involved in carcinogenesis and the development of resistance to methotrexate. This induction of drug resistance correlates with the relative efficiency of catecholestrogens in the generation of reactive oxygen species (ROS) and the induction of DNA strand breaks. Although antioxidants can neutralize ROS, the generation of these reactive species by catecholestrogens can be enhanced by electron donors like NADH. Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H2O2 generating system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential. In contrast, the GSH precursor NAC at low concentrations was able to enhance the level of oxidative damage, as observed with NADH. NAC can reduce Cu(II) to Cu(I) producing the radical NAC·, which can generate the superoxide anion. However, the importance of this pathway appears to be relatively minor since the addition of NAC to the 4-hydroxyestradiol/Cu(II) system generates about 15 times more DNA strand breaks than NAC and Cu(II) alone. We suggest that NAC can perpetuate the redox cycle between the quinone and the semiquinone forms of the catecholestrogens, thereby enhancing the production of ROS. In conclusion, this study demonstrates the crucial importance of the choice of antioxidant as potential therapy against the negative biological effects of estrogens.

KW - Antioxidants

KW - Breast cancer

KW - Catecholestrogen

KW - Free radicals

KW - Glutathione

KW - Hydroxyestrogen

KW - N-acetylcysteine

UR - http://www.scopus.com/inward/record.url?scp=0035190676&partnerID=8YFLogxK

U2 - 10.1016/S0891-5849(00)00446-9

DO - 10.1016/S0891-5849(00)00446-9

M3 - Article

VL - 30

SP - 62

EP - 73

JO - Free Radical Biology Medicine

JF - Free Radical Biology Medicine

SN - 0891-5849

IS - 1

ER -