Received for publication February 9, 2005.
Revised September 23, 2005.
Accepted for publication September 23, 2005.

Inhibition and recovery of rat hepatic glutathione S-transferase zeta and alteration of tyrosine metabolism following dichloroacetate exposure and withdrawal

Abstract

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 (MAAI), an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/d) 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/d) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following sub-chronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 µg, 2.5 µg, 250 µg or 50 mg DCA/kg/d 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 significantly decreased in a dose-dependent manner by 12 weeks exposure. Enzyme activity and expression decreased 95% after one week administration of high dose DCA. Eight weeks after cessation of high dose DCA, GSTz activity had returned to control levels, while protein expression remained 30% below control. At the 2.5 or 250 µg/kg/d doses, enzyme activity also decreased after 8 weeks exposure and returned to control levels one week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60-75 µg/kg/24h in animals exposed to 50 mg/kg/d 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.

Key words: drug toxicity, glutathione transferases

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