A pharmacodynamically responsive model of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) transfer between liver and fat at low and high doses.
We have constructed a pharmacokinetic model for TCDD in the rat, emphasizing its transfer between plasma, lipid, and cytoplasmic compartments of the liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Volumes of the lipid pools are controlled by a submodel of triglyceride (TG) metabolism and transport that responds via a receptor for TCDD in WAT cytoplasm with a Kd of about 2 nM. This submodel, and one for cytochrome P450IA2 induction, allowed us to simulate binding of TCDD to the induced P450IA2 binding sites at low doses (1 ng/kg to 10 micrograms/kg) independently of the decreased feed intake and hyperlipidemia associated with higher doses (20 to 120 micrograms/kg). In low-dose simulations, the induction of cytochrome P450IA2 binding sites for TCDD dominated the redistribution of TCDD between WAT and liver. When simulations were performed using a partitioning model with constant gastrointestinal flows, increased WAT lipolysis driven by reduced feed intake (from 10 to 120 micrograms/kg) is predicted to result in a decreased WAT volume and a sharp drop in the mass of WAT-associated TCDD, while initially increasing the levels of TCDD in liver. However, the observed concentration of TCDD in WAT increased in rats treated with a high dose (72 micrograms/kg) of TCDD. The rise in tissue concentrations could not be explained without incorporating decreased intestinal flows into the gastrointestinal absorption process, which increased the resorption of TCDD. TCDD concentrations in tissue increased only when the relative tissue volumes decreased more rapidly than the whole-body TCDD elimination rate.
Roth
W L
WL
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
Ernst
S
S
Weber
L W
LW
Kerecsen
L
L
Rozman
K K
KK
D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008433:Mathematics; D008954:Models, Biological; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D000072317:Polychlorinated Dibenzodioxins; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2