Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of hepatic microsomal enzymes. The influence of an inducing dose of TCDD on tissue distribution and other pharmacokinetic behavior of a TCDD analog in the mice was examined by employing a high specific activity radioligand. [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITCDD). Female C57BL/6J mice were pretreated with 0.1 mumol/kg of TCDD or the vehicle only, followed by 0.1 nmol ITCDD/kg 3 days later. The control animals had the highest concentration of ITCDD-derived radioactivity in the fat, but the TCDD-pretreated animals had the highest concentration in their livers. Whole-body elimination of ITCDD approximated first-order behavior, and induction by pretreatment with the inducing dose of TCDD almost doubled the rate of excretion (control mice, t1/2 = 14.2 days; pretreated mice, t1/2 = 8.0 days). All disposition results in naive and pretreated mice were satisfactorily described by a consistent physiologically based pharmacokinetic model (Leung et al., 1988a) in which induction increased the amount of microsomal ITCDD-binding protein from 1.75 to 20 nmol/liver and increased the rate constant for metabolism of free ITCDD from 1 to 3/hr/kg liver. The binding affinity of the microsomal ITCDD-binding protein was the same (20 nM) in both induced and noninduced mice. Model simulations indicated a time delay in the elimination of nonparent ITCDD metabolites from the body and a more rapid absorption of the parent ligand in the pretreated mice. Consistent with previous physiological modeling with TCDD in different mouse strains, the primary factor influencing the liver/fat concentration ratio appears to be the affinity and capacity of the microsomal TCDD-binding proteins, which are altered by induction. These dose-dependent pharmacokinetic differences with ITCDD are important considerations for TCDD risk assessment in which data from high dose rodent experiments are extrapolated to predict behavior at much lower environmental concentrations in exposed humans.

[1]  G. Lucier,et al.  Dioxin in soil: bioavailability after ingestion by rats and guinea pigs. , 1984, Science.

[2]  E. Glover,et al.  [125I]2-iodo-3,7,8-trichlorodibenzo-p-dioxin-binding species in mouse liver induced by agonists for the Ah receptor: characterization and identification. , 1989, Molecular pharmacology.

[3]  A. Okey,et al.  Cytosolic and nuclear binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to the Ah receptor in extra-hepatic tissues of rats and mice. , 1982, European journal of biochemistry.

[4]  R. A. Neal,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin tissue distribution, excretion, and effects on clinical chemical parameters in guinea pigs. , 1979, Toxicology and applied pharmacology.

[5]  H Falk,et al.  Health implications of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) contamination of residential soil. , 1984, Journal of toxicology and environmental health.

[6]  J. Olson.  Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs. , 1986, Toxicology and applied pharmacology.

[7]  S. Aust,et al.  Specific binding of polyhalogenated aromatic hydrocarbon inducers of cytochrome P-450d to the cytochrome and inhibition of its estradiol 2-hydroxylase activity. , 1987, Toxicology and applied pharmacology.

[8]  A. Schecter,et al.  Tissue distribution of dioxins and furans in humans from the general population , 1985 .

[9]  E. Glover,et al.  Stimulation of in vivo hepatic uptake and in vitro hepatic binding of [125I]2-lodo-3,7,8-trichlorodibenzo-p-dioxin by the administration of agonist for the Ah receptor. , 1989, Molecular pharmacology.

[10]  D. Paustenbach,et al.  Relative distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatic and adipose tissues. , 1990, Toxicology letters.

[11]  V. Wroblewski,et al.  Hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat and guinea pig. , 1985, Toxicology and applied pharmacology.

[12]  J. Olson,et al.  Relationship between the murine Ah phenotype and the hepatic uptake and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[13]  J. Q. Rose,et al.  The fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin following single and repeated oral doses to the rat. , 1976, Toxicology and applied pharmacology.

[14]  R. A. Neal,et al.  Tissue distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Golden Syrian hamster. , 1980, Toxicology and applied pharmacology.

[15]  D J Paustenbach,et al.  A physiologically based pharmacokinetic model for 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice. , 1988, Toxicology letters.

[16]  Nebert Dw,et al.  The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemicals by cytochrome P-450-mediated monooxygenases. , 1979 .

[17]  F. De Matteis,et al.  Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on drug metabolism and hepatic microsomes of rats and mice. , 1973, Environmental health perspectives.

[18]  J. Allen,et al.  Tissue distribution, excretion and biological effects of [14C]tetrachlorodibenzo-p-dioxin in rats. , 1975, Food and cosmetics toxicology.

[19]  D J Paustenbach,et al.  A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. , 1990, Toxicology and applied pharmacology.

[20]  R. A. Neal,et al.  Distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J, DBA/2J, and B6D2F1/J mice. , 1983, Drug metabolism and disposition: the biological fate of chemicals.

[21]  D. Nebert,et al.  Genetic regulation of aryl hydrocarbon hydroxylase induction. II. Simple Mendelian expression in mouse tissues in vivo. , 1972, The Journal of biological chemistry.

[22]  C. Bradfield,et al.  Kinetic and equilibrium studies of Ah receptor-ligand binding: use of [125I]2-iodo-7,8-dibromodibenzo-p-dioxin. , 1988, Molecular pharmacology.