A Pharmacodynamic Analysis of TCDD-Induced Cytochrome P450 Gene Expression in Multiple Tissues: Dose- and Time-Dependent Effects

Abstract

The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) to alter gene expression and the demonstration that the induction of CYP1A2 is responsible for hepatic TCDD sequestration suggest that both pharmacokinetic and pharmacodynamic events must be incorporated for a quantitative description of TCDD disposition. In this paper, a biologically based pharmacodynamic (BBPD) model for TCDD-induced biochemical responses in multiple tissues was developed. The parameters responsible for tissue response were estimated simultaneously with a refined physiologically based pharmacokinetic (PBPK) model developed by Wanget al.(1997a), by using the time-dependent effects of TCDD on induced CYP1A1/CYP1A2 gene expression in multiple target tissues (liver, lungs, kidneys, and skin) of female Sprague–Dawley rats treated with 10 μg TCDD/kg for 30 min, 1, 3, 8, or 24 h, or 7, 14, or 35 days. This refined BBPD model developed based on the time-course of TCDD-induced CYP1A1/CYP1A2 protein expression, and associated enzymatic activities well described the dose-dependent effects of TCDD on cytochrome P450 protein expression and associated enzyme activities in the multiple tissues of female Sprague–Dawley rats at 3 days following a single exposure to TCDD (0.01–30.0 μg TCDD/kg). This is the first BBPD model to quantitatively describe the time- and dose-dependent effects of TCDD on induced CYP1A1/CYP1A2 protein expression and associated enzyme activities in multiple target tissues for TCDD-induced biochemical responses.