Beland F A, McDaniel L P, Marques M M
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Carcinogenesis. 1999 Mar;20(3):471-7. doi: 10.1093/carcin/20.3.471.
Tamoxifen is a liver carcinogen in rats and has been associated with an increased risk of endometrial cancer in women. Recent reports of DNA adducts in leukocyte and endometrial samples from women treated with tamoxifen suggest that it may be genotoxic to humans. One of the proposed pathways for the metabolic activation of tamoxifen involves oxidation to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. In the present study, we compared the extent of DNA adduct formation in female Sprague-Dawley rats treated by gavage with seven daily doses of 54 micromol/kg tamoxifen or 4-hydroxytamoxifen and killed 24 h after the last dose. Liver weights and microsomal rates of ethoxyresorufin O-deethylation, 4-dimethylaminopyrine N-demethylation and p-nitrophenol oxidation were not altered by tamoxifen or 4-hydroxytamoxifen treatment. Uterine weights were decreased significantly and uterine peroxidase activity was decreased marginally in treated as compared with control rats. DNA adducts were assayed by 32P-post-labeling in combination with HPLC. Two major DNA adducts were detected in liver DNA from rats administered tamoxifen. These adducts had retention times comparable with those obtained from in vitro reactions of alpha-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide with DNA. Hepatic DNA adduct levels in rats administered 4-hydroxytamoxifen did not differ from those observed in control rats. Likewise, adduct levels in uterus DNA from rats treated with tamoxifen or 4-hydroxytamoxifen were not different from those detected in control rats. These data suggest that a metabolic pathway involving 4-hydroxytamoxifen is not a major pathway in the activation of tamoxifen to a DNA-binding derivative in Sprague-Dawley rats.
他莫昔芬是大鼠肝脏致癌物，且与女性子宫内膜癌风险增加有关。近期有关接受他莫昔芬治疗的女性白细胞和子宫内膜样本中DNA加合物的报道表明，它可能对人类具有基因毒性。他莫昔芬代谢活化的一种可能途径涉及氧化为4-羟基他莫昔芬，后者可能进一步氧化为亲电子的醌甲基化物。在本研究中，我们比较了经口强饲法给予七次每日剂量为54微摩尔/千克他莫昔芬或4-羟基他莫昔芬的雌性Sprague-Dawley大鼠在最后一剂后24小时处死时DNA加合物形成的程度。他莫昔芬或4-羟基他莫昔芬处理未改变肝脏重量以及乙氧异吩唑酮O-脱乙基化、4-二甲基氨基安替比林N-脱甲基化和对硝基苯酚氧化的微粒体速率。与对照大鼠相比，处理组大鼠子宫重量显著降低，子宫过氧化物酶活性略有降低。采用32P后标记结合高效液相色谱法检测DNA加合物。在给予他莫昔芬的大鼠肝脏DNA中检测到两种主要的DNA加合物。这些加合物的保留时间与α-乙酰氧基他莫昔芬和4-羟基他莫昔芬醌甲基化物与DNA的体外反应所得到的保留时间相当。给予4-羟基他莫昔芬的大鼠肝脏DNA加合物水平与对照大鼠中观察到的水平无差异。同样，用他莫昔芬或4-羟基他莫昔芬处理的大鼠子宫DNA中的加合物水平与对照大鼠中检测到的水平无差异。这些数据表明，在Sprague-Dawley大鼠中，涉及4-羟基他莫昔芬的代谢途径不是他莫昔芬活化为DNA结合衍生物的主要途径。
