Inhibition and induction of aromatase (CYP19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells
Inhibition and induction of aromatase (CYP19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells
复制标题
DOI：
10.1093/toxsci/kfi325
复制
发表时间：
2005-12-01
影响因子：
3.8
通讯作者：
van den Berg, M
中科院分区：
文献类型：
--
作者：
Cantón, RF;Sanderson, JT;van den Berg, M
溴化阻燃剂（BFR）是环境中普遍存在的持久性化学品，在野生动物和人类组织中的含量越来越高。先前对BFR类多溴二苯醚进行的体外研究表明，其具有干扰内分泌的特性。我们的研究评估了19种溴化二苯醚，5种羟基化溴化二苯醚（OH-BDEs），1种甲氧基化溴化二苯醚（CH 3 O-BDE）、四溴双酚A（TBBPA）、其二溴丙烷醚衍生物（TBBPA-DBPE）和溴化酚/苯甲醚2，4，6-三溴苯酚（TBP）、4-溴苯酚（4 BP）和2，4，6-三溴苯甲醚（TBA）对H295 R人肾上腺皮质癌细胞中类固醇生成酶芳香酶（CYP 19）的催化活性。在0.5至7.5 μ M的浓度范围内研究了影响;暴露时间为24小时。6-OH-BDE 47和6-OH-BDE 99分别在浓度>2.5 μ M和>5 μ M时对芳香酶活性显示出抑制作用。然而，当浓度大于2.5 μ M时，6-OH-BDE 47也会导致细胞毒性在统计学上显著增加（根据线粒体MTT还原和乳酸脱氢酶渗漏[LDH]），这可以部分解释对芳香酶活性的明显抑制作用。与6-OH-BDE 47相比，甲氧基类似物（6-CH 3 O-BDE 47）没有引起细胞毒性效应，但仍然对芳香酶具有显著抑制作用。TBP在0.5和7.5 μ M之间引起芳香酶活性的浓度依赖性诱导（在7.5 μ M时最大诱导3.8倍）。当OH-基团取代CH 3 O-基团或当与该OH-基团相邻的溴原子不存在时，未观察到这种诱导。这些体外研究结果提供了更详细的构效关系的研究基础，这些溴代化合物和芳香化酶活性的调制。
Brominated flame retardants (BFRs) are persistent and ubiquitous chemicals in the environment, and they are found at increasing levels in tissues of wildlife and humans. Previous in vitro studies with the BFR class of polybrominated diphenyl ethers (BDEs) have shown endocrine-disrupting properties. Our study assessed the potential effects of nineteen BDEs, five hydroxylated BDEs (OH-BDEs), one methoxylated BDE (CH3O-BDE), tetrabromobisphenol-A (TBBPA), its dibromopropane ether derivative (TBBPA-DBPE), and the brominated phenols/anisols 2,4,6-tribromophenol (TBP), 4-bromophenol (4BP) and 2,4,6-tribromoanisole (TBA) on the catalytic activity of the steroidogenic enzyme aromatase (CYP19) in H295R human adrenocortical carcinoma cells. Effects were studied in the concentration range from 0.5 to 7.5 mu M; exposures were for 24 h. Both 6-OH-BDE47 and 6-OH-BDE99 showed an inhibitory effect on aromatase activity at concentrations >2.5 mu M and >5 mu M, respectively. However, 6-OH-BDE47 also caused a statistically significant increase in cytotoxicity (based on mitochondrial MTT reduction and lactate dehydrogenase-leakage [LDH]) at concentrations >2.5 mu M that could explain in part the apparent inhibitory effect on aromatase activity. Compared to 6-OH-BDE47, the methoxy analog (6-CH3O-BDE47) did not elicit a cytotoxic effect, whereas significant inhibition of aromatase remained. TBP caused a concentration-dependent induction of aromatase activity between 0.5 and 7.5 mu M (with a maximum of 3.8-fold induction at 7.5 mu M). This induction was not observed when a OH- group replaced the CH3O- group or when bromine atoms adjacent to this OH- group were absent. These in vitro results provide a basis for studies of more detailed structure-activity relationships between these brominated compounds and the modulation of aromatase activity.