Mutagenic activity of 4-hydroxyestradiol, but not 2-hydroxyestradiol, in BB rat2 embryonic cells, and the mutational spectrum of 4-hydroxyestradiol.
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.
New York University Dental School, New York, New York 10010, USA.
Zhonglin
Z
Zhao
Wieslawa
W
Kosinska
Michael
M
Khmelnitsky
Ercole L
EL
Cavalieri
Eleanor G
EG
Rogan
Dhrubajyoti
D
Chakravarti
Peter G
PG
Sacks
Joseph B
JB
Guttenplan
D000818:Animals; D002396:Catechols / Q000737:chemistry; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D002393:Estrogens, Catechol; D007202:Indicators and Reagents; D016296:Mutagenesis; D009153:Mutagens; D051381:Rats; D011913:Rats, Inbred BB; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002396:Catechols; D002393:Estrogens, Catechol; D007202:Indicators and Reagents; D009153:Mutagens; D004958:Estradiol; D004247:DNA; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol