Marques M M, Beland F A
Centro de Química Estrutural, Instituto Superior Técnico, Lisboa, Portugal.
Carcinogenesis. 1997 Oct;18(10):1949-54. doi: 10.1093/carcin/18.10.1949.
Tamoxifen is a liver carcinogen in rats and has been shown to increase the risk of endometrial cancer in women. Recent reports of DNA adducts in leucocyte and endometrial samples from women treated with tamoxifen indicate 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 show that 4-hydroxytamoxifen quinone methide reacts with DNA to form covalent adducts. The major products, which result from 1,8-addition of the exocyclic nitrogen of deoxyguanosine to the conjugated system of 4-hydroxytamoxifen quinone methide, are characterized as (E)- and (Z)-alpha-(deoxyguanosin-N2-yl)-4-hydroxytamoxifen.
他莫昔芬在大鼠中是一种肝脏致癌物，并且已被证明会增加女性患子宫内膜癌的风险。最近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加合物的报告表明，它可能对人类具有基因毒性。他莫昔芬代谢活化的一种推测途径涉及氧化为4-羟基他莫昔芬，其可能进一步氧化为亲电子的醌甲基化物。在本研究中，我们表明4-羟基他莫昔芬醌甲基化物与DNA反应形成共价加合物。主要产物是由脱氧鸟苷的环外氮原子与4-羟基他莫昔芬醌甲基化物的共轭体系进行1,8-加成反应产生的，其特征为（E）-和（Z）-α-（脱氧鸟苷-N2-基）-4-羟基他莫昔芬。
