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ToxSci Advance Access originally published online on September 16, 2004
Toxicological Sciences 2004 82(2):381-393; doi:10.1093/toxsci/kfh276
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.

A Quantitative Description of Suicide Inhibition of Dichloroacetic Acid in Rats and Mice

Deborah A. Keys1,*, Irvin R. Schultz{dagger}, Deirdre A. Mahle{ddagger} and Jeffrey W. Fisher*

* Department of Environmental Health Science, University of Georgia, Athens, Georgia 30602; {dagger} Battelle, Pacific Northwest Division, Sequim, Washington 98382; and {ddagger} ManTech Environmental Technology, Inc., Dayton, Ohio 45437

Received June 10, 2004; accepted September 7, 2004

Dichloroacetic acid (DCA), a minor metabolite of trichloroethylene (TCE) and water disinfection byproduct, remains an important risk assessment issue because of its carcinogenic potency. DCA has been shown to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta (GSTzeta). To better predict internal dosimetry of DCA, a physiologically based pharmacokinetic (PBPK) model of DCA was developed. Suicide inhibition was described dynamically by varying the rate of maximal GSTzeta-mediated metabolism of DCA (Vmax) over time. Resynthesis (zero-order) and degradation (first-order) of metabolic activity were described. Published iv pharmacokinetic studies in naïve rats were used to estimate an initial Vmax value, with Km set to an in vitro determined value. Degradation and resynthesis rates were set to estimated values from a published immunoreactive GSTzeta protein time course. The first-order inhibition rate, kd, was estimated to this same time course. A secondary, linear non-GSTzeta-mediated metabolic pathway is proposed to fit DCA time courses following treatment with DCA in drinking water. The PBPK model predictions were validated by comparing predicted DCA concentrations to measured concentrations in published studies of rats pretreated with DCA following iv exposure to 0.05 to 20 mg/kg DCA. The same model structure was parameterized to simulate DCA time courses following iv exposure in naïve and pretreated mice. Blood and liver concentrations during and postexposure to DCA in drinking water were predicted. Comparisons of PBPK model predicted to measured values were favorable, lending support for the further development of this model for application to DCA or TCE human health risk assessment.

Key Words: (3–6) DCA; PBPK; GSTzeta; suicide inhibition; rat; mouse.


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