Oda T, Aizu-Yokota E, Kitaoka M, Sato Y
Kyoritsu College of Pharmacy, Tokyo, Japan.
Biol Pharm Bull. 1995 Jun;18(6):818-24. doi: 10.1248/bpb.18.818.
We report the effects of indenestrol A, a metabolite of diethylstilbestrol, and its analogue, indenestrol B, on the relative plating efficiency and cellular microtubular architecture of Chinese hamster V79 cells. In this study, the effects of the monomethyl ethers of indenestrols A and B on these biological activities and their affinity for estrogen receptors in cytosol from mouse uteri were investigated. The results indicate that among eight optically active and four racemic methyl ethers, the 4'-methyl ether of [(-)-3S]indenestrol B exhibits both the strongest cytotoxicity in, and greatest disruption of, the cellular microtubular architecture of Chinese hamster V79 cells in culture. For the 6- and 4'-monomethyl ethers of optically active indenestrols A and B, some correlation was found between cytotoxicity and the effect on the distribution of cellular microtubular networks in Chinese hamster V79 cells. Estrogen receptor competitive binding studies revealed that stereochemistry and the position (6 or 4') of the methyl ether group contributed greatly to their binding affinity. However, no correlation was observed between the affinity for estrogen receptors and the cytotoxicity of the monomethyl ester tested. This suggests that the important causes of cytotoxicity in this series of compounds involve the inhibitory activity on cellular microtubule networks and not the affinity for estrogen receptors.
我们报告了己烯雌酚的代谢产物茚雌酚A及其类似物茚雌酚B对中国仓鼠V79细胞相对接种效率和细胞微管结构的影响。在本研究中，研究了茚雌酚A和B的单甲醚对这些生物学活性及其与小鼠子宫胞质溶胶中雌激素受体亲和力的影响。结果表明，在8种旋光性和4种外消旋甲醚中，[(-)-3S]茚雌酚B的4'-甲醚在培养的中国仓鼠V79细胞中表现出最强的细胞毒性和对细胞微管结构的最大破坏。对于旋光性茚雌酚A和B的6-和4'-单甲醚，在中国仓鼠V79细胞中发现细胞毒性与对细胞微管网络分布的影响之间存在一些相关性。雌激素受体竞争性结合研究表明，立体化学和甲醚基团的位置（6或4'）对其结合亲和力有很大贡献。然而，在所测试的单甲酯中，未观察到对雌激素受体的亲和力与细胞毒性之间的相关性。这表明该系列化合物中细胞毒性的重要原因涉及对细胞微管网络的抑制活性，而非对雌激素受体的亲和力。
