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ToxSci Advance Access published online on September 16, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh276
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 10, 2004
Accepted September 7, 2004

Biotransformation and Toxicokinetics

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

Deborah A. Keys 1*, Irvin R. Schultz 2, Deirdre A. Mahle 3, and Jeffrey W. Fisher 1

1 Department of Environmental Health Science, University of Georgia, Athens, GA 30602
2 Battelle, Pacific Northwest Division, Richland, Washington
3 Man Tech Environmental Technology, Inc., Dayton, Ohio 45437

* To whom correspondence should be addressed. E-mail: dkeys{at}uga.edu.


  Abstract

Dichloroacetic acid (DCA), a minor metabolite of trichloroethylene 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 pharmacokin etic model of DCA was developed. Suicide inhibition was described dyn amically by vary ing 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 naïv e 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 pre-treated 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 pre-treated mice. Blood and liver concentrations during and post-exposure to DCA in drinking water were predicted. Comparisons of PBPK model predicted to measured values were favorable lending suppo rt for the further development of this model for application to DCA or TCE human health risk assessment.

Keywords: (3-6) DCA; PBPK; GSTzeta; suicide inhibition; rat; mouse.
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