N-acetylcysteine blocks formation of cancer-initiating estrogen-DNA adducts in cells.
Catechol estrogens, especially 4-hydroxylated metabolites of 17beta-estradiol (E(2)), are responsible for estrogen-induced carcinogenesis. 4-Hydroxyestradiol (4-OHE(2)), a major metabolite of E(2) formed preferentially by cytochrome P-450 1B1, is oxidized to E(2)-3,4-quinone, which can react with DNA to yield the depurinating adducts 4-OHE(2)-1-N3Ade and 4-OHE(2)-1-N7Gua. The apurinic sites generated by the loss of these depurinating adducts induce mutations that could lead to cancer initiation. In this study, we have evaluated the effects of N-acetylcysteine (NAcCys) on the metabolism of two cell lines, MCF-10F (a normal human breast epithelial cell line) and E6 (a normal mouse mammary epithelial cell line), treated with 4-OHE(2) or its reactive metabolite, E(2)-3,4-quinone. Extensive HPLC with electrochemical detection and UPLC-MS/MS analyses of the cell media demonstrated that the presence of NAcCys very efficiently shifted the estrogen metabolism toward protective methoxylation and conjugation pathways in multiple ways, whereas formation of depurinating DNA adducts was inhibited. Protection by NAcCys seems to be similar in both cell lines, irrespective of their origin (human or mouse) or the presence of estrogen receptor-alpha. This finding suggests that NAcCys, a common dietary supplement, could be used as a potential chemopreventive agent to block the initial step in the genotoxicity caused by catechol estrogen quinones.
Zahid
Muhammad
M
Eppley Institute for Research in Cancer and Allied Diseases, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Saeed
Muhammad
M
Ali
Mohammed F
MF
Rogan
Eleanor G
EG
Cavalieri
Ercole L
EL
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000517:prevention & control; D002460:Cell Line; D018736:DNA Adducts / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000378:metabolism*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control; D051379:Mice
D000975:Antioxidants; D018736:DNA Adducts; D002393:Estrogens, Catechol; C500988:estradiol-3,4-quinone; D004958:Estradiol; C014036:4-hydroxyestradiol; D000111:Acetylcysteine
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