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Thiols can either enhance or suppress DNA damage induction by catecholestrogens
P A Thibodeau1, S Kocsis-Bédard, J Courteau
1Department of Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Free Radical Biology & Medicine
|January 3, 2001
Summary
Certain thiol agents like GSH can protect against estrogen-induced DNA damage. However, N-acetylcysteine (NAC) may unexpectedly increase damage by enhancing reactive oxygen species (ROS) generation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Estrogen metabolites, catecholestrogens, are implicated in cancer development and methotrexate resistance.
- Catecholestrogen-induced drug resistance is linked to reactive oxygen species (ROS) generation and DNA strand breaks.
- Antioxidants can mitigate ROS, but electron donors like NADH can enhance ROS production by catecholestrogens.
Purpose of the Study:
- To investigate the impact of various thiol agents on DNA damage induced by a 4-hydroxyestradiol/Cu(II) system.
- To determine if thiol agents inhibit or enhance oxidative DNA damage mediated by catecholestrogens.
Main Methods:
- Utilized a hydrogen peroxide (H2O2) generating system involving 4-hydroxyestradiol and copper(II) ions.
- Assessed the effects of different thiol agents: glutathione (GSH), N-acetylcysteine (NAC), dithiothreitol (DTT), and dihydrolipoic acid (DHLA).
- Quantified DNA strand breaks to evaluate the protective or damaging effects of the thiol agents.
Main Results:
- GSH, DTT, and DHLA demonstrated inhibitory effects on 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH being most effective.
- NAC, a GSH precursor, enhanced oxidative DNA damage at low concentrations, similar to NADH.
- NAC's pro-oxidant effect is attributed to reducing Cu(II) to Cu(I), generating a NAC radical and superoxide anion, and potentially perpetuating catecholestrogen redox cycling.
Conclusions:
- The choice of antioxidant is critical for therapeutic strategies targeting the adverse biological effects of estrogens.
- While some thiols offer protection, others like NAC may exacerbate estrogen-induced oxidative stress and DNA damage.
- Understanding these differential effects is crucial for developing effective cancer therapies and managing drug resistance.