Thiols can either enhance or suppress DNA damage induction by catecholestrogens

The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involv ed in carcinogenesis and the development of resistance to methotrexate. Thi s induction of drug resistance correlates with the relative efficiency of c atecholestrogens 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 enhanc ed by electron donors like NADH. Therefore, this study was undertaken to de termine the ability of different thiol agents (GSH, NAG, DTT, DHLA) to eith er inhibit or enhance the level of DNA damage induced by the H2O2 generatin g system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHL A inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA dam age, with GSH showing the best potential. In contrast, the GSH precursor NA C 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 NAG(.), which can generate the superoxide anion. However, the importance o f 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 stra nd 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 catechole strogens, thereby enhancing the production of ROS. In conclusion, this stud y demonstrates the crucial importance of the choice of antioxidant as poten tial therapy against the negative biological effects of estrogens. (C) 2000 Elsevier Science Inc.