Liu Ju, Liu Hong, van Breemen Richard B, Thatcher Gregory R J, Bolton Judy L
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231, USA.
Chem Res Toxicol. 2005 Feb;18(2):174-82. doi: 10.1021/tx0497752.
Although approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer in women. With an understanding of the potential carcinogenic mechanisms of these compounds, SERMs could in principle be designed or selected for use that avoids these problems. Acolbifene (EM-652) is a fourth-generation SERM and the active form of the ester prodrug EM-800. As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue. However, acolbifene was found in this investigation to form two kinds of quinone methides, either through chemical or through enzymatic oxidation. One was a classical acolbifene quinone methide, which was formed by oxidation at the C-17 methyl group, and the other was a diquinone methide involving the oxidation of two phenol groups. The half-life of the classical quinone methide was determined to be 32 +/- 0.4 s at physiological pH and temperature. The quinone methides reacted with glutathione (GSH) to form five mono-GSH conjugates and five di-GSH conjugates. The majority of GSH conjugates resulted from reaction of the classical acolbifene quinone methide with GSH. Incubations of acolbifene with GSH and either tyrosinase or human and rat liver microsomes also produced acolbifene quinone methide-GSH conjugates. In addition to reaction with GSH, the classical acolbifene quinone methide was also shown to react with deoxynucleosides. One of the major deoxynucleoside adducts was identified as the deoxyadenosine adduct resulting from reaction of the classical acolbifene quinone methide with the exocyclic amino group of adenine. Acolbifene could also induce DNA damage in the S30 breast cancer cell line. These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene.
尽管选择性雌激素受体调节剂（SERM）他莫昔芬已被批准用于治疗激素依赖性乳腺癌以及预防高危女性患乳腺癌，但它与女性子宫内膜癌风险增加有关。随着对这些化合物潜在致癌机制的了解，原则上可以设计或选择使用能避免这些问题的SERM。阿考比芬（EM - 652）是一种第四代SERM，也是酯前药EM - 800的活性形式。作为乳腺肿瘤发生和生长的纯拮抗剂，阿考比芬不会刺激子宫内膜组织。然而，在本研究中发现阿考比芬通过化学或酶促氧化形成两种醌甲基化物。一种是经典的阿考比芬醌甲基化物，由C - 17甲基氧化形成，另一种是涉及两个酚羟基氧化的双醌甲基化物。在生理pH和温度下，经典醌甲基化物的半衰期测定为32±0.4秒。醌甲基化物与谷胱甘肽（GSH）反应形成五种单GSH缀合物和五种双GSH缀合物。大多数GSH缀合物是由经典阿考比芬醌甲基化物与GSH反应产生的。阿考比芬与GSH以及酪氨酸酶或人和大鼠肝微粒体一起孵育也产生阿考比芬醌甲基化物 - GSH缀合物。除了与GSH反应外，经典阿考比芬醌甲基化物还显示与脱氧核苷反应。主要的脱氧核苷加合物之一被鉴定为经典阿考比芬醌甲基化物与腺嘌呤的环外氨基反应产生的脱氧腺苷加合物。阿考比芬还可诱导S30乳腺癌细胞系中的DNA损伤。这些数据表明经典的亲电阿考比芬醌甲基化物可能是阿考比芬潜在毒性的原因。
