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.
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, 920-0934 Kanazawa, Japan.
Kei
K
Takemoto
Miki
M
Nakajima
Yuto
Y
Fujiki
Miki
M
Katoh
Frank J
FJ
Gonzalez
Tsuyoshi
T
Yokoi
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