Dose-dependent elevation of Ah receptor binding by TCDD in rat liver

Changes in [3H]TCDD binding to unoccupied liver Ah receptor were examined following chronic or acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to adult female Sprague-Dawley rats. Chronic biweekly administration of TCDD equivalent to 0, 10, 30, or 100 ng/kg/day TCDD for 22 weeks caused dose-dependent increases in liver TCDD concentration, aryl hydrocarbon hydroxylase (AHH) induction, and [3H]TCDD binding to unoccupied cytosolic Ah receptor sites. Maximal increases (twofold) of cytosolic receptor binding occurred at an estimated dose of slightly greater than 30 ng/kg/day. The increase in [3H]TCDD binding was half-maximal at an estimated dose of approximately 17 ng/kg/day which produced a liver concentration of 1.5 ppb TCDD. Cytosolic [3H]TCDD binding in control and treated animals sedimented mainly in the 8-9 S region of sucrose density gradients with a minor peak sedimenting in the 4-5 S region. Binding was markedly elevated in the 8-9 S region of cytosols from the TCDD-induced rats; however, TCDD treatment had no affect on [3H]TCDD binding in the 4-5 S region. Saturation and Scatchard analyses of Ah receptor binding showed no apparent changes in Kd following chronic TCDD treatment; however, a twofold increase in the number of unoccupied Ah receptor binding sites was observed. Neither aging nor ovariectomy significantly changed measurable cytosolic Ah receptor binding in control animals. When adult female rats were administered a single dose of TCDD (6 micrograms/kg) an initial drop (approximately 40%) in cytosolic receptor binding was observed at 30 and 60 min, followed by a steady increase in binding up to 250% of controls 9 days after TCDD treatment.