The AAPS Journal, 2012, 14(2):329-344.

Role of Metabolism in the Effects of Genistein and Its Phase II Conjugates on the Growth of Human Breast Cell Lines

Bo Yuan, Linglan Wang, Yi Jin, et al

Department of Pharmaceutical Analysis, Pharmacy School, Shenyang Pharmaceutical University, Shenyang, 110016 China; et al

Genistein has been investigated for several decades for its potential role in breast cancer prevention. Previous researches have shown that glucuronide and sulfate conjugates are the major species circulating in the blood after genistein ingestion. It was hypothesized that enzymes (UDP-glucuronosyltransferases, sulphotransferases, β-glucuronidases, and sulphatases) present in breast tissues would catalyze the inter-conversion between the aglycone and the conjugates in situ. Therefore, our aim was to investigate how genistein, genistein-7-glucuronide (G-7-G), genistein-7-sulfate (G-7-S), and 4'-sulfate (G-4'-S) were metabolized in mammary cells and to determine the effects of metabolism on their proliferative actions using cultured breast cell lines. As expected, genistein stimulated the cell growth of breast cancer cells (MCF-7 and T47D) concentration-dependently at lower concentrations but inhibited their growth at higher concentration. It showed low activities in a non-tumorigenic cell line (MCF-10A) due to the absence of ERα. Genistein was extensively metabolized to glucuronides by MCF-7 and to sulfates by T47D, while it was poorly metabolized by MCF-10A. G-7-G displayed weak stimulation activity in breast cancer cells. G-7-G underwent extensive metabolism in T47D and MCF-10A but not in MCF-7. The proliferative effects of G-7-G on MCF-7 and T47D were associated with its hydrolysis to genistein in these cells. In contrast, G-7-S and G-4'-S were not metabolized by these three cells and had no effects on their growth. In conclusion, production of phase II metabolites did not affect the proliferation effect of genistein on MCF-7 and T47D. Deconjugation was correlated to the apparent proliferative effects of G-7-G in breast cancer cells.

美国《美国药物科学家杂志》，2012年6月

金雀异黄素及其二期共轭物的药物代谢对人体乳腺癌细胞生长的作用

袁博、 王玲兰、 金逸等

中国沈阳药科大学药学院制药分析部门等

金雀异黄素在预防乳腺癌方面的潜在作用已被调查了数十年。以往的研究表明，在摄入金雀异黄素后葡萄糖醛酸和硫酸结合物成为血液循环的主要物质。假设，目前在乳腺癌组织中的酶 （尿苷二磷酸葡醛酸转移酶、磺基转移酶、β-葡萄糖醛酸酶、硫酸盐）会催化糖苷配基及其轭合物之间的原位转换。因此，我们的目的是使用体外培养的乳腺癌细胞，探讨金雀异黄素、 金雀异黄素-7-葡萄糖醛酸 (G-7-G)、 金雀异黄素-7-硫酸酯 (G-7-S) 和 4'-硫酸盐 (G-4'-S)是如何在乳腺细胞中代谢的，并确定代谢对细胞增殖活性的影响。不出所料，在低浓度下金雀异黄素以浓度依赖的方式刺激乳腺癌细胞生长 （MCF-7 和 T47D），而在较高浓度时抑制细胞的生长。它表明非致瘤细胞(MCF-10A) 的低活性是由于ERα 的缺失。金雀异黄素被MCF-7广泛地代谢为葡萄糖醛酸甙，被T47D代谢为硫酸盐，而它们几乎不被 MCF-10A代谢。G-7-G 在乳腺癌细胞中显示微弱的刺激活性。G-7-G 在T47D 和 MCF 10A细胞中 经历了广泛代谢但在 MCF-7中没有。G-7-G 对 MCF-7 和 T47D的 增殖作用均与其在这些细胞中水解为金雀异黄素有关。相比之下，G-7-S 和 G-4'-S 在这些细胞中不被代谢因此对其生长没有影响。总之， II 期代谢产物不影响金雀异黄素对 MCF-7 和 T47D的 增殖作用。降解与乳腺癌细胞中G-7-G的明显增殖效应有关。