Moore M, Mustain M, Daniel K, Chen I, Safe S, Zacharewski T, Gillesby B, Joyeux A, Balaguer P
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
Toxicol Appl Pharmacol. 1997 Jan;142(1):160-8. doi: 10.1006/taap.1996.8022.
Several hydroxylated polychlorinated biphenyls (PCBs) identified in human serum have been synthesized and these include 2,2',3,4',5,5'-hexachloro-4-biphenylol; 2,3,3',4',5-pentachloro-4-biphenylol; 2',3,3',4',5-pentachloro-4-biphenylol; 2,2',3,3',4',5-hexachloro-4-biphenylol; 2,2',3,3',4',5,5'-heptachloro-4-biphenylol; 2,2',3,4',5,5',6-heptachloro-4-biphenylol; and 2,2',3',4,4',5,5'-heptachloro-3-biphenylol. The hydroxy-PCBs exhibited minimal binding to the rat uterine cytosolic estrogen receptor (ER) and did not induce proliferation of estrogen-responsive MCF-7 human breast cancer cells at concentrations ranging from 10(-5) to 10(-8) M. The estrogenic activity of these compounds was further investigated utilizing two estrogen-responsive in vitro bioassays, namely, (i) HeLa cells stably transfected with a Gal4:human ER chimera and a 17-mer-regulated luciferase reporter gene, and (ii) MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a chloramphenicol acetyl transferase (CAT) reporter gene. None of the hydroxy-PCBs significantly induced luciferase activity in the stably transfected HeLa cells or CAT activity in MCF-7 cells at concentrations as high as 10(-5) M. The antiestrogenic effects of the hydroxy-PCBs were also investigated using the same bioassays in which the cells were cotreated with 17beta-estradiol plus the hydroxy-PCBs. All of the hydroxy-PCB congeners inhibited one or more estrogenic response, and one congener, 2,2',3,4',5,5',6-heptachloro-4-biphenylol, inhibited 17beta-estradiol-induced cell proliferation and CAT activity in MCF-7 cells and luciferase activity in HeLa cells.
已合成了在人血清中鉴定出的几种羟基化多氯联苯（PCBs），其中包括2,2',3,4',5,5'-六氯-4-联苯酚；2,3,3',4',5-五氯-4-联苯酚；2',3,3',4',5-五氯-4-联苯酚；2,2',3,3',4',5-六氯-4-联苯酚；2,2',3,3',4',5,5'-七氯-4-联苯酚；2,2',3,4',5,5',6-七氯-4-联苯酚；以及2,2',3',4,4',5,5'-七氯-3-联苯酚。羟基化多氯联苯与大鼠子宫胞质雌激素受体（ER）的结合力极小，在浓度范围为10^(-5)至10^(-8) M时，不会诱导雌激素反应性MCF-7人乳腺癌细胞增殖。利用两种雌激素反应性体外生物测定法进一步研究了这些化合物的雌激素活性，即：（i）稳定转染了Gal4:人ER嵌合体和17聚体调控的荧光素酶报告基因的HeLa细胞，以及（ii）瞬时转染了全长人ER表达质粒和含有与氯霉素乙酰转移酶（CAT）报告基因相连的雌激素反应性卵黄蛋白原A2启动子的质粒的MCF-7细胞。在浓度高达10^(-5) M时，没有一种羟基化多氯联苯能在稳定转染的HeLa细胞中显著诱导荧光素酶活性，或在MCF-7细胞中诱导CAT活性。还使用相同的生物测定法研究了羟基化多氯联苯的抗雌激素作用，在这些生物测定法中，细胞用17β-雌二醇加羟基化多氯联苯共同处理。所有羟基化多氯联苯同系物均抑制一种或多种雌激素反应，其中一种同系物2,2',3,4',5,5',6-七氯-4-联苯酚抑制17β-雌二醇诱导的MCF-7细胞增殖和CAT活性以及HeLa细胞中的荧光素酶活性。
