Tsutsui Takeki, Tamura Yukiko, Yagi Eiichi, Someya Hitomi, Hori Itsuro, Metzler Manfred, Barrett J Carl
Department of Pharmacology, The Nippon Dental University, School of Dentistry at Tokyo, Tokyo, Japan.
Int J Cancer. 2003 Jun 20;105(3):312-20. doi: 10.1002/ijc.11046.
For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of phytoestrogens, the abilities of 5 phytoestrogens, daidzein, genistein, biochanin A, prunetin, and coumestrol, to induce cell transformation and genetic effects were examined using the Syrian hamster embryo (SHE) cell model. Cellular growth was inhibited by all phytoestrogens in a concentration-related manner. The growth inhibitory effect of the compounds was ranked: genistein, prunetin > coumestrol > biochanin A > daidzein, which did not correspond to their apoptosis-inducing abilities. Morphological transformation in SHE cells was elicited by all phytoestrogens, except, prunetin. The transforming activities were ranked as follows: genistein > coumestrol > daidzein > biochanin A. Somatic mutations in SHE cells at the Na(+)/K(+) ATPase and hprt loci were induced only by genistein, coumestrol, or daidzein. Chromosome aberrations were induced by genistein or coumestrol, and aneuploidy in the near diploid range was occurred by genistein or biochanin A. Genistein, biochanin A or daidzein induced DNA adduct formation in SHE cells with the abilities: genistein > biochanin A > daidzein. Prunetin was negative for any of these genetic endpoints. Our results provide evidence that genistein, coumestrol, daidzein and biochanin A induce cell transformation in SHE cells and that the transforming activities of these phytoestrogens correspond to at least 2 of the mutagenic effects by each phytoestrogen, i.e., gene mutations, chromosome aberrations, aneuploidy or DNA adduct formation, suggesting the possible involvement of mutagenicity in the initiation of phytoestrogen-induced carcinogenesis.
为了同时评估植物雌激素的体外致癌性和致突变性，使用叙利亚仓鼠胚胎（SHE）细胞模型检测了5种植物雌激素（大豆苷元、染料木黄酮、鹰嘴豆芽素A、樱黄素和香豆雌酚）诱导细胞转化和遗传效应的能力。所有植物雌激素均以浓度相关的方式抑制细胞生长。这些化合物的生长抑制作用排序为：染料木黄酮、樱黄素＞香豆雌酚＞鹰嘴豆芽素A＞大豆苷元，这与它们的诱导凋亡能力不相符。除樱黄素外，所有植物雌激素均能诱导SHE细胞发生形态转化。转化活性排序如下：染料木黄酮＞香豆雌酚＞大豆苷元＞鹰嘴豆芽素A。仅染料木黄酮、香豆雌酚或大豆苷元能诱导SHE细胞在Na(+)/K(+) ATP酶和次黄嘌呤-鸟嘌呤磷酸核糖转移酶（hprt）位点发生体细胞突变。染料木黄酮或香豆雌酚能诱导染色体畸变，染料木黄酮或鹰嘴豆芽素A能导致近二倍体范围内的非整倍体出现。染料木黄酮、鹰嘴豆芽素A或大豆苷元能诱导SHE细胞形成DNA加合物，能力排序为：染料木黄酮＞鹰嘴豆芽素A＞大豆苷元。樱黄素在所有这些遗传终点检测中均为阴性。我们的结果表明，染料木黄酮、香豆雌酚、大豆苷元和鹰嘴豆芽素A能诱导SHE细胞发生转化，并且这些植物雌激素的转化活性与每种植物雌激素至少两种诱变效应相对应，即基因突变、染色体畸变、非整倍体或DNA加合物形成，这表明诱变性可能参与了植物雌激素诱导的致癌作用起始过程。
