PT  - JOURNAL ARTICLE
AU  - Guo, Xu
AU  - Dixit, Vaishali
AU  - Liu, Huiping
AU  - Shroads, Albert L.
AU  - Henderson, George N.
AU  - James, Margaret O.
AU  - Stacpoole, Peter W.
TI  - INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONE <em>S</em>-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL
AID  - 10.1124/dmd.105.003996
DP  - 2006 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 36--42
VI  - 34
IP  - 1
4099  - http://dmd.aspetjournals.org/content/34/1/36.short
4100  - http://dmd.aspetjournals.org/content/34/1/36.full
SO  - Drug Metab Dispos2006 Jan 01; 34
AB  - Dichloroacetate (DCA) is an investigational drug for certain metabolic disorders, a by-product of water chlorination and a metabolite of certain industrial solvents and drugs. DCA is biotransformed to glyoxylate by glutathione S-transferase zeta (GSTz1-1), which is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/day) decrease the activity and expression of GSTz1-1, which alters tyrosine metabolism and may cause hepatic and neurological toxicity. The effect of environmental DCA doses (μg/kg/day) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following subchronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 μg, 2.5 μg, 250 μg, or 50 mg DCA/kg/day in drinking water for up to 12 weeks. Recovery was followed after the 8-week exposure. GSTz specific activity and protein expression (Western immunoblotting) were decreased in a dose-dependent manner by 12 weeks of exposure. Enzyme activity and expression decreased 95% after a 1-week administration of high-dose DCA. Eight weeks after cessation of high-dose DCA, GSTz activity had returned to control levels. At the 2.5 or 250 μg/kg/day doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60 to 75 μg/kg/24 h in animals exposed to 50 mg/kg/day DCA. The liver/body weight ratio increased in the high-dose group after 8 weeks of DCA. These studies demonstrate that short-term administration of DCA inhibits rat liver GSTz across the wide concentration range to which humans are exposed. The American Society for Pharmacology and Experimental Therapeutics