TY - JOUR
T1 - Antioxidant inhibits tamoxifen-DNA adducts in endometrial explant culture
AU - Sharma, Minoti
AU - Shubert, David E.
AU - Sharma, Moheswar
AU - Rodabaugh, Kerry J.
AU - McGarrigle, Barbara P.
AU - Vezina, Chad M.
AU - Bofinger, Diane P.
AU - Olson, James R.
PY - 2003/7/18
Y1 - 2003/7/18
N2 - Fresh human endometrial explants were incubated for 24h at 37°C with either tamoxifen (10-100μM) or the vehicle (0.1% ethanol). Three metabolites namely, α-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the α-hydroxytamoxifen pathway were detected using authentic α-(deoxyguanosyl-N2) tamoxifen standards. Relative DNA-adduct levels of 2.45, 1.12, and 0.44 per 106 nucleotides were detected following incubations with 100, 25, and 10μM tamoxifen, respectively. The concurrent exposure of the explants to 100μM tamoxifen with 1mM ascorbic acid reduced the level of α-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen-DNA adducts detectable in the explants from the same specimens exposed to 100μM 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.
AB - Fresh human endometrial explants were incubated for 24h at 37°C with either tamoxifen (10-100μM) or the vehicle (0.1% ethanol). Three metabolites namely, α-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the α-hydroxytamoxifen pathway were detected using authentic α-(deoxyguanosyl-N2) tamoxifen standards. Relative DNA-adduct levels of 2.45, 1.12, and 0.44 per 106 nucleotides were detected following incubations with 100, 25, and 10μM tamoxifen, respectively. The concurrent exposure of the explants to 100μM tamoxifen with 1mM ascorbic acid reduced the level of α-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen-DNA adducts detectable in the explants from the same specimens exposed to 100μM 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.
KW - Antioxidant
KW - Explant culture
KW - Human endometrial tissue
KW - Tamoxifen metabolites
KW - Tamoxifen-DNA adducts
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U2 - 10.1016/S0006-291X(03)01134-3
DO - 10.1016/S0006-291X(03)01134-3
M3 - Article
C2 - 12849995
AN - SCOPUS:0038387788
VL - 307
SP - 157
EP - 164
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -