Stimulation of in vivo hepatic uptake and in vitro hepatic binding of [125I]2-lodo-3,7,8-trichlorodibenzo-p-dioxin by the administration of agonist for the Ah receptor.
[125I]2-lodo-3,7,8-trichlorodibenzo-p-dioxin ([125I]Cl3DpD), a radiolabeled, isosteric, analogue of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was synthesized and used to study in vivo tissue localization and in vivo tissue binding. Twenty-four hours after the administration of a tracer dose (1 X 10(-10) mol/kg) of [125I] Cl3DpD to C57BL/6J mice, the hepatic concentration of radioactivity was 1-2% of the administered dose, whereas in mice pretreated with TCDD (1 X 10(-7) mol/kg), the hepatic accumulation of radiolabel was 25-30% of that administered. Liver homogenate from TCDD-treated mice bound 4 to 10 times more [125I]Cl3DpD than homogenate from control mice. The enhancement of in vivo uptake and in vitro tissue binding of [125I]Cl3DpD by TCDD administration was confined to liver and was not observed in other tissues examined, kidney, lung, spleen, small intestines, and muscle. The administration of TCDD to C57BL/6J mice produces dose-related stimulation of in vivo hepatic uptake of [125I]Cl3DpD, binding of radioligand to liver homogenate, and hepatic aryl hydrocarbon hydroxylase activity, with the dose for half-maximal stimulation, ED50, varying from 1.5 to 4.0 x 10(-9) mol/kg. In congenic C57BL/6J (Ahd/Ahd) mice, which express the lower affinity Ah receptor, the ED50 values for all three responses were shifted to approximately 10-fold higher doses. 3,3',4,4',5,5'-Hexabromobiphenyl, a weak agonist for the Ah receptor produced a dose-related stimulation of these three responses in C57BL/6J mice (ED50 values of approximately 5 X 10(-7) mol/kg), but was without effect in C57BL/6J (Ahd/Ahd) mice. Stimulation of vivo hepatic uptake and in vitro liver homogenate binding of [125I]Cl3DpD was produced by administration of Ah agonists, such as 2,3,7,8-tetrachlorodibenzofuran and beta-naphthoflavone, but inactive congeners and other compounds that do not act via the Ah receptor, e.g. phenobarbital and pregnenolone-16 alpha-carbonitrile, did not evoke these effects. Thus, TCDD and other Ah agonists act through the Ah receptor to increase a liver binding species that increases the hepatic uptake of [125I]Cl3DpD in vivo and binding of this radioligand to liver homogenate in vitro.
Poland
A
A
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706.
Teitelbaum
P
P
Glover
E
E
Kende
A
A
D000818:Animals; D004147:Dioxins / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects*
D004147:Dioxins; D007457:Iodine Radioisotopes; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; C060352:2-iodo-3,7,8-trichlorodibenzo-4-dioxin