Activation of 4-hydroxytamoxifen and the tamoxifen derivative metabolite E by uterine peroxidase to form DNA adducts: comparison with DNA adducts formed in the uterus of Sprague-Dawley rats treated with tamoxifen.
Daily intraperitoneal treatment of female Sprague-Dawley rats with either 5, 10 or 20 mg/kg tamoxifen (TAM) for 1 week increased the level of peroxidase activity in the uterus 2- to 10-fold compared to the control level. Using uterine extracts prepared from control and TAM treated animals, we investigated the activation of 4-hydroxytamoxifen (4-HO-TAM) and (E,Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene (cis/trans-metabolite E) to form DNA adducts. Activation of 4-HO-TAM by uterine extracts prepared from either control or TAM-treated rats produced one major (a) and two minor DNA (b and c) adducts. A similar activation of cis/trans-metabolite E produced two adducts (d and e). There was good correlation between levels of uterine peroxidase activity and levels of DNA adducts formed by 4-HO-TAM and cis/trans-metabolite E. Activation of 4-HO-TAM and cis/trans-metabolite E with horseradish peroxidase (HRP) produced the same adducts as observed by activation with uterine extract. Treatment of Sprague-Dawley rats with 5 and 10 mg/kg for 7 days produced eleven DNA adducts in the liver with no adducts detected in the uterus. However, treatment of rats with 20 mg/kg of TAM for 7 days produced the same adduct pattern in the liver and also one major adduct (1) in the uterus with a relative adduct level of 6.4 - 4.1 x 10(-9). Tamoxifen-DNA adduct 1 detected both in the liver and in the uterus of treated rats was similar to adducts produced by activation of 4-HO-TAM with either uterine extract or HRP. The results of these studies suggest a general model whereby the tamoxifen metabolite 4-HO-TAM is further activated in the uterus by peroxidase enzymes to form DNA adducts.
Pathak
D N
DN
Brain Tumor Research Center of the Department of Neurological Surgery, University of California, San Francisco 94143-0806, USA.
Pongracz
K
K
Bodell
W J
WJ
D000475:Alkenes / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006735:Horseradish Peroxidase / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D015394:Molecular Structure; D010544:Peroxidases / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014599:Uterus / Q000201:enzymology*
D000475:Alkenes; D018736:DNA Adducts; D010636:Phenols; D013629:Tamoxifen; C016601:afimoxifene; C090768:1-(4-hydroxyphenyl)-1,2-diphenyl-1-butene; D006735:Horseradish Peroxidase; D010544:Peroxidases