Differential Time–Course and Dose–Response Relationships of TCDD-Induced CYP1B1, CYP1A1, and CYP1A2 Proteins in Rats

Abstract

This study examined the relationship between dose- and time-dependent hepatic localization of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and expression of CYP1B1, CYP1A1 and CYP1A2 proteins. A dose-dependent increase in hepatic TCDD in female Sprague-Dawley rats treated with 0.01-30.0 μg TCDD/kg was observed. TCDD induced CYP1A1 protein in rats treated with 0.3 μg TCDD/kg or higher. TCDD induced CYP1A2 and CYP1B1 proteins in rats treated with 1.0 μg TCDD/kg or higher. Thein vivoED50(μg TCDD/kg) for TCDD-induced CYP1A1, CYP1A2 and CYP1B1 proteins were 0.22, 0.40 and 5.19, respectively. Hepatic accumulation of TCDD reached a maximum at 8 hours post dosing with a t1/2of approximately 10 days. TCDD-induced CYP1A1/CYP1A2 protein expression was increased time-dependently, reaching a maximum at 3 days after dosing and remaining elevated for 35 days. In contrast, TCDD-induced CYP1B1 protein showed significant expression at 3 days after dosing and decreased to basal concentrations by 35 days. This study demonstrates that TCDD exhibits differential dose-response and time-course relationships on hepatic localization and cytochrome P-450 protein expression.