Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The role of aryl hydrocarbon receptor (AhR) and cytochrome P450 (Cyp) 1 family in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) was investigated in vivo. Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (-/-) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13). Uterine wet weight and uterine peroxidase activity (UPA) were measured as markers of estrogen responsiveness. UPA was a better marker of estrogen responsiveness than the uterine wet weight. In AhR wild-type (+/+) mice, UPA (208.1+/-81.6 units/g tissue) was increased by the administration of E2 (to 297.2+/-178.7 units/g). The administration of TCDD significantly ( p<0.01) decreased the UPA (10.5+/-3.4 units/g) compared with that in the control mice. Co-administration of TCDD with E2 also significantly ( p<0.05) decreased the UPA (18.8+/-19.9 units/g) compared with that in E2-treated mice. In AhR(-/-) mice, UPA (162.9+/-146.7 units/g) was significantly ( p<0.01) increased by the administration of E2 (486.8+/-108.2 units/g). In contrast to the results in AhR(+/+) mice, UPA was not affected by the administration of TCDD (51.8+/-70.6 units/g) compared with control, and co-administration of TCDD with E2 (545.8+/-189.4 units/g) compared with that in E2-treated mice. In Cyp1a2/1b1(+/+) mice, UPA was significantly ( p<0.05) increased by the administration of E2 (70.0+/-36.4 units/g). Co-administration of TCDD with E2 significantly ( p<0.05) decreased the UPA (29.6+/-22.2 units/g) compared with that in E2-treated mice. In Cyp1a2(-/-) mice, co-administration of TCDD with E2 significantly ( p<0.01) decreased the UPA (6.8+/-5.1 units/g) compared with that in E2-treated mice. In Cyp1b1(-/-) mice, UPA (5.5+/-8.1 units/g) was significantly ( p<0.05) increased by the administration of E2 (56.6+/-34.1 units/g). In contrast to the results in Cyp1a2/1b1(+/+) mice or Cyp1a2(-/-) mice, UPA was not affected by the co-administration of TCDD and E2 (52.6+/-30.1 units/g) compared with that in E2-treated mice. This is the first demonstration that Cyp1b1 as well as AhR is involved in the antiestrogenic effects of TCDD.
Takemoto
Kei
K
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, 920-0934 Kanazawa, Japan.
Nakajima
Miki
M
Fujiki
Yuto
Y
Katoh
Miki
M
Gonzalez
Frank J
FJ
Yokoi
Tsuyoshi
T
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000502:physiology*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000502:physiology; D065633:Cytochrome P-450 CYP1B1; D004785:Environmental Pollutants / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism / Q000493:pharmacokinetics*; D020847:Estrogen Receptor Modulators / Q000633:toxicity*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology
D004785:Environmental Pollutants; D020847:Estrogen Receptor Modulators; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D004958:Estradiol; D009195:Peroxidase; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1