A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice

Toxicological Sciences : an Official Journal of the Society of Toxicology
Deborah A KeysJeffrey W Fisher

Abstract

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 naive 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 p...Continue Reading

Citations

Apr 25, 2007·Journal of Toxicology and Environmental Health. Part a·Ahmad MirfazaelianJeffrey W Fisher
May 15, 2007·Journal of Toxicology and Environmental Health. Part a·Ahmad Mirfazaelian, Jeffrey W Fisher
Sep 13, 2006·Environmental Health Perspectives·Weihsueh A ChiuMarina V Evans
Jan 5, 2010·Toxicology and Applied Pharmacology·Jessica L MatthewsRonald L Melnick

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