Antioxidant inhibits tamoxifen-DNA adducts in endometrial explant culture.
Fresh human endometrial explants were incubated for 24h at 37 degrees C with either tamoxifen (10-100 micro M) or the vehicle (0.1% ethanol). Three metabolites namely, alpha-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the alpha-hydroxytamoxifen pathway were detected using authentic alpha-(deoxyguanosyl-N(2)) tamoxifen standards. Relative DNA-adduct levels of 2.45, 1.12, and 0.44 per 10(6) nucleotides were detected following incubations with 100, 25, and 10 micro M tamoxifen, respectively. The concurrent exposure of the explants to 100 micro M tamoxifen with 1mM ascorbic acid reduced the level of alpha-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen-DNA adducts detectable in the explants from the same specimens exposed to 100 micro M tamoxifen with 1mM ascorbic acid were also inhibited. These results support the role of oxidative biotransformation of tamoxifen in the subsequent formation of DNA adducts in this tissue.
Sharma
Minoti
M
Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. minoti.sharma@roswellpark.org
Shubert
David E
DE
Sharma
Moheswar
M
Rodabaugh
Kerry J
KJ
McGarrigle
Barbara P
BP
Vezina
Chad M
CM
Bofinger
Diane P
DP
Olson
James R
JR
D000328:Adult; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism*; D046508:Culture Techniques; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D004965:Estrogen Antagonists / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism*
D000975:Antioxidants; D018736:DNA Adducts; D004965:Estrogen Antagonists; D013629:Tamoxifen; D004247:DNA; D001205:Ascorbic Acid