QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.003996v1 34/1/36    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guo, X. Articles by Stacpoole, P. W. Search for Related Content PubMed PubMed Citation Articles by Guo, X. Articles by Stacpoole, P. W.

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONE S-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Division of Endocrinology and Metabolism, Department of Medicine (X.G., H.L., A.L.S., G.N.H., P.W.S.) and Department of Biochemistry and Molecular Biology (P.W.S.), College of Medicine; and Department of Medicinal Chemistry, College of Pharmacy (V.D., M.O.J.), University of Florida, Gainesville, Florida

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doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn.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.

This article has been cited by other articles:

				A. L. Shroads, X. Guo, V. Dixit, H.-P. Liu, M. O. James, and P. W. Stacpoole Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1163 - 1171. [Abstract] [Full Text] [PDF]

				M. Jia, B. Coats, M. Chadha, B. Frentzen, J. Perez-Rodriguez, P. A. Chadik, R. A. Yost, G. N. Henderson, and P. W. Stacpoole Human Kinetics of Orally and Intravenously Administered Low-Dose 1,2-13C-Dichloroacetate. J. Clin. Pharmacol., December 1, 2006; 46(12): 1449 - 1459. [Abstract] [Full Text] [PDF]