Byford J R, Shaw L E, Drew M G B, Pope G S, Sauer M J, Darbre P D
Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, University of Reading, Reading RG6 6AJ, UK.
J Steroid Biochem Mol Biol. 2002 Jan;80(1):49-60. doi: 10.1016/s0960-0760(01)00174-1.
Parabens (4-hydroxybenzoic acid esters) have been recently reported to have oestrogenic activity in yeast cells and animal models. Since the human population is exposed to parabens through their widespread use as preservatives in foods, pharmaceuticals and cosmetics, we have investigated here whether oestrogenic activity of these compounds can also be detected in oestrogen-sensitive human cells. We report on the oestrogenic effects of four parabens (methylparaben, ethylparaben, n-propylparaben, n-butylparaben) in oestrogen-dependent MCF7 human breast cancer cells. Competitive inhibition of [3H]oestradiol binding to MCF7 cell oestrogen receptors could be detected at 1,000,000-fold molar excess of n-butylparaben (86%), n-propylparaben (77%), ethyl-paraben (54%) and methylparaben (21%). At concentrations of 10(-6)M and above, parabens were are able to increase expression of both transfected (ERE-CAT reporter gene) and endogenous (pS2) oestrogen-regulated genes in these cells. They could also increase proliferation of the cells in monolayer culture, which could be inhibited by the antiestrogen ICI 182,780, indicating that the effects were mediated through the oestrogen receptor. However, no antagonist activity of parabens could be detected on regulation of cell proliferation by 17 beta-oestradiol at 10(-10)M. Molecular modelling has indicated the mode by which paraben molecules can bind into the ligand binding pocket of the crystal structure of the ligand binding domain (LBD) of the oestrogen receptor alpha (ERalpha) in place of 17beta-oestradiol; it has furthermore shown that two paraben molecules can bind simultaneously in a mode in which their phenolic hydroxyl groups bind similarly to those of the meso-hexoestrol molecule. Future work will need to address the extent to which parabens can accumulate in hormonally sensitive tissues and also the extent to which their weak oestrogenic activity can add to the more general environmental oestrogen problem.
对羟基苯甲酸酯（4-羟基苯甲酸酯）最近被报道在酵母细胞和动物模型中具有雌激素活性。由于人类通过在食品、药品和化妆品中广泛用作防腐剂而接触到对羟基苯甲酸酯，我们在此研究了在雌激素敏感的人类细胞中是否也能检测到这些化合物的雌激素活性。我们报告了四种对羟基苯甲酸酯（甲基对羟基苯甲酸酯、乙基对羟基苯甲酸酯、正丙基对羟基苯甲酸酯、正丁基对羟基苯甲酸酯）对雌激素依赖性MCF7人乳腺癌细胞的雌激素作用。在正丁基对羟基苯甲酸酯（86%）、正丙基对羟基苯甲酸酯（77%）、乙基对羟基苯甲酸酯（54%）和甲基对羟基苯甲酸酯（21%）摩尔过量1000000倍时，可检测到[3H]雌二醇与MCF7细胞雌激素受体结合的竞争性抑制。在浓度为10(-6)M及以上时，对羟基苯甲酸酯能够增加这些细胞中转染的（雌激素反应元件-氯霉素乙酰转移酶报告基因）和内源性的（pS2）雌激素调节基因的表达。它们还能增加单层培养细胞的增殖，这可被抗雌激素ICI 182,780抑制，表明这些作用是通过雌激素受体介导的。然而，在10(-10)M时，未检测到对羟基苯甲酸酯对17β-雌二醇调节细胞增殖的拮抗活性。分子模拟表明了对羟基苯甲酸酯分子能够取代17β-雌二醇结合到雌激素受体α（ERα）配体结合域（LBD）晶体结构的配体结合口袋中的方式；此外，还表明两个对羟基苯甲酸酯分子可以以其酚羟基与内消旋己雌酚分子的酚羟基类似的方式同时结合。未来的工作需要解决对羟基苯甲酸酯在激素敏感组织中积累的程度，以及它们微弱的雌激素活性在多大程度上会加剧更普遍的环境雌激素问题。
