Nakagawa Y, Tayama K
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, Tokyo 169-0073, Japan.
Arch Toxicol. 2001 Apr;75(2):74-9. doi: 10.1007/s002040100225.
The estrogenic activity of benzophenone and its metabolites, benzhydrol and p-hydroxybenzophenone, were investigated in vitro by estrogen receptor (ER) competitive ligand binding assay and in vivo by uterotrophic assay in juvenile female Sprague-Dawley (SD) rats. p-Hydroxybenzophenone as well as diethylstilbestrol and bisphenol A, known xeno-estrogenic compounds, competed with fluorescein-labeled 17 beta-estradiol to bind human recombinant ER alpha in a concentration-dependent manner. Fifty percent inhibitory values (IC50) of diethylstilbestrol, bisphenol A, and p-hydroxybenzophenone were approximately 10(-8), 10(-5), and 5 x 10(-5) M, respectively. However, neither the parent compound nor benzhydrol at concentrations from 10(-9) to 5 x 10(-4) M impaired the binding of 17 beta-estradiol to ER alpha. Juvenile female rats (21-days-old) were given s.c. injections of benzophenone, its metabolites, and 17 beta-estradiol for 3 days. Administration of p-hydroxybenzophenone (100-400 mg/kg) elicited an increase in absolute and relative uterine weights in a dose-dependent manner and 17 beta-estradiol (10 micrograms/kg) increased uterine weight approximately fourfold relative to control. The uterine response caused by both compounds was accompanied by an increase in luminal epithelial height and stromal cells in the uterus and an increase in thickness of vaginal epithelial cell layers with cornification. In contrast, benzophenone and benzhydrol at a dose of 400 mg/kg affected neither uterine weight nor histological changes of the uterus and vagina. These results indicate that p-hydroxybenzophenone, a metabolite of benzophenone, exhibits intrinsic xeno-estrogenic activity in the female reproductive tract.
通过雌激素受体（ER）竞争性配体结合试验在体外研究了二苯甲酮及其代谢产物二苯甲醇和对羟基二苯甲酮的雌激素活性，并通过子宫增重试验在幼年雌性斯普拉格-道利（SD）大鼠体内进行了研究。对羟基二苯甲酮以及已知的外源性雌激素化合物己烯雌酚和双酚A，以浓度依赖的方式与荧光素标记的17β-雌二醇竞争结合人重组ERα。己烯雌酚、双酚A和对羟基二苯甲酮的50%抑制值（IC50）分别约为10^(-8)、10^(-5)和5×10^(-5) M。然而，浓度为10^(-9)至5×10^(-4) M的母体化合物和二苯甲醇均未损害17β-雌二醇与ERα的结合。给幼年雌性大鼠（21日龄）皮下注射二苯甲酮、其代谢产物和17β-雌二醇，持续3天。给予对羟基二苯甲酮（100 - 400 mg/kg）以剂量依赖的方式引起绝对子宫重量和相对子宫重量增加，而17β-雌二醇（10微克/千克）使子宫重量相对于对照组增加约四倍。这两种化合物引起的子宫反应伴随着子宫腔上皮高度和基质细胞增加以及阴道上皮细胞层厚度增加并伴有角质化。相比之下，剂量为400 mg/kg的二苯甲酮和二苯甲醇对子宫重量和子宫及阴道的组织学变化均无影响。这些结果表明，二苯甲酮的代谢产物对羟基二苯甲酮在雌性生殖道中表现出内在的外源性雌激素活性。
