Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. Export

@article{citeulike:1404871, abstract = {Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E(2)) is thought to be oxidized to 4-hydroxyestradiol and then to E(2)-3,4-quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E(2)-3,4-quinone can undergo redox cycling with E(2)-3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E(2)-3,4-quinone are carcinogenic or mutagenic in several systems, 4-hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-hydroxyestradiol is mutagenic in the cII assay in BB rat2 cells. Under similar conditions, 2-hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E(2)-3,4-quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.}, address = {New York University Dental School, New York, New York 10010, USA.}, author = {Zhao, Z. and Kosinska, W. and Khmelnitsky, M. and Cavalieri, E. L. and Rogan, E. G. and Chakravarti, D. and Sacks, P. G. and Guttenplan, J. B.}, citeulike-article-id = {1404871}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/tx0502645}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/tx0502645}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16544955}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16544955}, doi = {10.1021/tx0502645}, issn = {0893-228X}, journal = {Chem Res Toxicol}, keywords = {2-hydroxyoestradiol, 4-hydroxyoestradiol, bb\_rat2\_cells, embyronic\_cells, mutagenicity, mutational\_spectrum, oestrogen}, month = {March}, number = {3}, pages = {475--479}, posted-at = {2007-06-22 16:33:42}, priority = {2}, title = {Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol.}, url = {http://dx.doi.org/10.1021/tx0502645}, volume = {19}, year = {2006} }

TY - JOUR ID - citeulike:1404871 L3 - citeulike-article-id:1404871 N2 - Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations. In this latter process, estradiol (E(2)) is thought to be oxidized to 4-hydroxyestradiol and then to E(2)-3,4-quinone, which reacts with DNA leading to apurinic sites. These sites represent premutagenic lesions. Additionally, E(2)-3,4-quinone can undergo redox cycling with E(2)-3,4-hydroquinone, leading to the release of reactive oxygen species. Although there is evidence that estradiol and E(2)-3,4-quinone are carcinogenic or mutagenic in several systems, 4-hydroxyestradiol, a key intermediate in the proposed genotoxic pathway, has thus far been negative in mutagenesis assays. Another major metabolite of estradiol, 2-hydroxyestradiol, is essentially inactive in carcinogenicity or mutagenicity assays. Here, we report that when using multiple low-dose exposures 4-hydroxyestradiol is mutagenic in the cII assay in BB rat2 cells. Under similar conditions, 2-hydroxyestradiol is inactive. Furthermore, the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs, consistent with the known ability of E(2)-3,4-quinone to form a significant fraction of DNA adducts at adenines. Thus, the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway. IS - 3 JF - Chem Res Toxicol SN - 0893-228X AD - New York University Dental School, New York, New York 10010, USA. EP - 479 TI - Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol. VL - 19 SP - 475 KW - 2-hydroxyoestradiol KW - 4-hydroxyoestradiol KW - bb_rat2_cells KW - embyronic_cells KW - mutagenicity KW - mutational_spectrum KW - oestrogen AU - Zhao, Z AU - Kosinska, W AU - Khmelnitsky, M AU - Cavalieri, EL AU - Rogan, EG AU - Chakravarti, D AU - Sacks, PG AU - Guttenplan, JB PY - 2006/03// UR - http://dx.doi.org/10.1021/tx0502645 ER -