Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: quantitative structure-activity relationships.
The concentration-dependent effects of several PCB, PCDD, and PCDF congeners and several commercial PCB preparations as antiestrogens were determined in the aryl hydrocarbon (Ah)-responsive MCF-7 human breast cancer cell lines. The inhibition of the 17 beta-estradiol-induced secretion of the 52-kDa protein (procathepsin D) was measured using a combination of polyacrylamide gel electrophoresis, double-staining of the protein bands with ISS ProBlue and silver stain, and quantitation by densitometric analysis. For the PCBs, the order of antiestrogenic potency was 3,3',4,4',5-pentachlorobiphenyl > 3,3',4,4',5,5'-hexachlorobiphenyl approximately 3,3',4,4'-tetrachlorobiphenyl > 2,3,3',4,4',5'-hexa, 2,3,3',4,4'- and 2,3,4,4',5-pentachlorobiphenyl > Aroclors 1221, 1232, 1248, 1254, and 1260 were inactive as antiestrogens at the highest concentrations used in this study (10(-6) M). For the PCDDs and PCDFs, the order of antiestrogenic potency was 2,3,7,8-tetrachlorodibenzo-p-dioxin > 2,3,7,8-tetrachlorodibenzofuran > 2,3,4,7,8-pentachlorodibenzofuran > 1,2,3,7,9-pentachlorodibenzofuran > 1,3,6,8-tetrachlorodibenzofuran. With few exceptions, the order of potency for all these congeners and mixtures paralleled their relative activities as agonists for other Ah receptor-mediated responses and their competitive binding affinities for the Ah receptor. The results of this study support the role for the Ah receptor in mediating the inhibition of the 17 beta-estradiol-induced secretion of the 52-kDa protein in MCF-7 cells and also points out the utility of this technique as a bioassay for this class of compounds.
Krishnan
V
V
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843.
Safe
S
S
D001140:Aroclors / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D003720:Densitometry; D004147:Dioxins / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D013194:Staining and Labeling; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D001140:Aroclors; D001572:Benzofurans; D004147:Dioxins; D004965:Estrogen Antagonists; D009363:Neoplasm Proteins; D004958:Estradiol; C023614:dibenzofuran; D011078:Polychlorinated Biphenyls; C020887:dibenzo(1,4)dioxin