A Pharmacodynamic Analysis of TCDD-Induced Cytochrome P450 Gene Expression in Multiple Tissues: Dose- and Time-Dependent Effects
| Autor: | Xiaofeng Wang, Michael J. Santostefano, David G. Ross, Linda S. Birnbaum, Vicki M. Richardson, Michael J. DeVito |
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| Rok vydání: | 1998 |
| Předmět: |
endocrine system
medicine.medical_specialty Physiologically based pharmacokinetic modelling Polychlorinated Dibenzodioxins Time Factors Toxicology Models Biological Isozyme Gene Expression Regulation Enzymologic Rats Sprague-Dawley Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A2 Internal medicine Gene expression Cytochrome P-450 CYP1A1 medicine Animals heterocyclic compounds reproductive and urinary physiology Pharmacology Regulation of gene expression Dose-Response Relationship Drug biology CYP1A2 Cytochrome P450 Rats stomatognathic diseases Dose–response relationship Endocrinology Liver Organ Specificity Toxicity biology.protein Female Oxidoreductases |
| Zdroj: | Toxicology and Applied Pharmacology. 151:294-310 |
| ISSN: | 0041-008X |
| Popis: | 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 Wang et 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 microgram 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 micromgram 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. |
| Databáze: | OpenAIRE |
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