DIFFERENTIAL TIME-COURSE AND DOSE-RESPONSE RELATIONSHIPS OF TCDD-INDUCED CYP1B1, CYP1A1, AND CYP1A2 PROTEINS IN RATS

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 in crease in hepatic TCDD in female Sprague-Dawley rats treated with 0.01 -30.0 mu g TCDD/kg was observed, TCDD induced CYP1A1 protein in rats t reated with 0.3 mu g TCDD/kg or higher, TCDD induced CYP1A2 and CYP1B1 proteins in rats treated with 1.0 mu g TCDD/kg or higher, The in vivo ED50 (mu g TCDD/kg) for TCDD-induced CYP1A1, CYP1A2 and CYP1B1 protei ns were 0.22, 0.40 and 5.19, respectively. Hepatic accumulation of TCD D reached a maximum at 8 hours post dosing with a t(1/2) of approximat ely 10 days, TCDD-induced CYP1A1/CYP1A2 protein expression was increas ed time-dependently, reaching a maximum at 3 days after dosing and rem aining 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 exh ibits differential dose-response and time-course relationships on hepa tic localization and cytochrome P-450 protein expression. (C) 1997 Aca demic Press.