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

Journal Article · Thu Sep 16 04:00:00 EDT 2004 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfh276· OSTI ID:860059

Keys, Deborah A; Schultz, Irv R; Mahle, Deirdre A; Fisher, Jeffrey W

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 native 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 native 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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 860059
• Report Number(s): PNWD-SA-6816
• Journal Information: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 2 Vol. 82; ISSN 1096-6080; ISSN TOSCF2
• Country of Publication: United States
• Language: English

Related Subjects

(3–6) DCA
59 BASIC BIOLOGICAL SCIENCES
BIOLOGICAL PATHWAYS
BLOOD
DATA
DOSIMETRY
DRINKING WATER
GLUTATHIONE
GSTzeta
IN VITRO
LIVER
METABOLISM
METABOLITES
MICE
PBPK
PROTEINS
RISK ASSESSMENT
STERILIZATION
TRANSFERASES
WATER
rat.
suicide inhibition