Effects of several dioxin-like compounds on estrogen metabolism in the malignant MCF-7 and nontumorigenic MCF-10A human mammary epithelial cell lines.
In human breast tissue, estrone (E(1)) and estradiol (E(2)) are mainly hydroxylated by cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) to 2-hydroxyestrogens (2-OHE(1/2)) and 4-hydroxyestrogens (4-OHE(1/2)), respectively. Several studies show that 4-OHE(1/2), but not 2-OHE(1/2), may act as a carcinogen and a high estrogen 4-/2-hydroxylation ratio appears to be a marker for the presence of neoplasms. In this study, we investigated the effects of several dioxin-like compounds on estrogen 2- and 4-hydroxylation in a malignant (MCF-7) and a nontumorigenic (MCF-10A) human mammary epithelial cell line. 2- and 4-methoxyestrogen (MeOE(1/2)) formations were used as measures of the 2- and 4-hydroxylation pathways, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 3,3'4,4',5,5'-hexachlorobiphenyl (PCB 169) concentration dependently induced 2-MeOE(1/2) formation and ethoxyresorufin-O-deethylation (EROD) activity through induced CYP1A1 expression in MCF-7 and MCF-10A cells. 2,3',4,4',5-pentachlorobiphenyl (PCB 118) had no such effect. Effects on CYP1B1 expression and 4-MeOE(1/2) formation were less pronounced; only TCDD caused an induction, whereas PCB 169 was a potent and selective inhibitor of 4-MeOE(1/2) formation (IC(50) 0.7 and 2.2 nM PCB 169 in MCF-7 and MCF-10A cells, respectively). MCF-10A cells were less responsive toward dioxin-like compounds and the apparent EC(50) values for CYP1A1 and CYP1B1 induction in this study were 10-100 fold higher than in MCF-7 cells. The constitutive 4-/2-MeOE(1/2) ratios were 2.99 +/- 0.78 and 0.93 +/- 0.40 in MCF-7 and MCF-10A, respectively. Incubation with dioxin-like compounds resulted in a concentration-dependent decrease in the 4-/2-MeOE(1/2) ratio, but an increase in potentially carcinogenic estrogen metabolites in both MCF-7 and MCF-10A cells. This indicates that even though the 4-/2-OHE(1/2) ratio may be used as indicator for the presence of neoplasms, it is readily lowered by dioxin-like compounds and its value as a prognostic parameter for cancer risk should be further examined.
van Duursen
Majorie B M
MB
Institute for Risk Assessment Sciences (IRAS), Utrecht University, The Netherlands. M.vanDuursen@iras.uu.nl
Sanderson
J Thomas
JT
van der Bruggen
Marieke
M
van der Linden
Jeroen
J
van den Berg
Martin
M
D000077584:2-Methoxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001572:Benzofurans / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000378:metabolism; D001940:Breast / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D004147:Dioxins / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D006801:Humans; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity
D001572:Benzofurans; D014408:Biomarkers, Tumor; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; C045018:4-methoxyestradiol; D004958:Estradiol; D000077584:2-Methoxyestradiol; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C038890:2,3,4,7,8-pentachlorodibenzofuran