Antiestrogens and the formation of DNA damage in rats: a comparison.
Tamoxifen (TAM) has been used as an agent for the treatment and prevention of breast cancer. However, long-term treatment of TAM in women increases the risk of developing endometrial cancer. The secondary cancer may be due to the genotoxicity of TAM. To find safer alternatives, four selective estrogen receptor modulators (SERMs), 4-hydroxytamoxifen (4-OHTAM), toremifene (TOR), raloxifene (RAL), and ICI 182,780, were administered to rats with an equimolar dose of TAM [54 micromol/kg (20 mg/kg)/day, p.o. for 7 days]. To evaluate the genotoxicity of each SERM, the presence of bulky DNA adducts was determined by (32)P-postlabeling/polyacrylamide gel electrophoresis and (32)P-postlabeling/high-performance liquid chromatography. The formation of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) was analyzed as a marker of typical oxidative damage, using liquid chromatography electrospray tandem mass spectrometry. Among the SERMs, bulky DNA adducts were detected in the livers of rats treated with TAM; the total amount of TAM-DNA adducts was 26.1 adducts/10(7) nucleotides. However, with a detection limit of approximately 2 adducts/10(9) nucleotides, no bulky DNA adducts were observed with 4-OHTAM, TOR, RAL, or ICI 182,780. In addition, no significant increase of hepatic 8-oxodG lesions was detected in rats treated with any of the antiestrogens. Therefore, TOR, RAL, and ICI 182,780 are likely to be less genotoxic than TAM.
Kim
Sung Yeon
SY
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, 11794-8651, USA.
Suzuki
Naomi
N
Laxmi
Y R Santosh
YR
Umemoto
Atsushi
A
Matsuda
Tomonari
T
Shibutani
Shinya
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000235:genetics; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats
D018736:DNA Adducts; D020847:Estrogen Receptor Modulators; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine