Dichloroacetate (DCA) is an investigational drug for certain metabolic diseases. It is biotransformed principally by the -1 family isoform of glutathione transferase (GSTz1), also known as maleylacetoacetate isomerase (MAAI), which catalyzes the penultimate step in tyrosine catabolism. DCA causes a reversible peripheral neuropathy in several species, including humans. However, recent clinical trials indicate that adults are considerably more susceptible to this adverse effect than children. We evaluated the kinetics and biotransformation of DCA and its effects on tyrosine metabolism in nine patients treated for 6 months with 25 mg/kg/day and in rats treated for 5 days with 50 mg/kg/day. We also measured the activity and expression of hepatic GSTz1/MAAI. Chronic administration of DCA causes a striking age-dependent decrease in its plasma clearance and an increase in its plasma half-life in patients and rats. Urinary excretion of unchanged DCA in rats increases with age, whereas oxalate, an end product of DCA metabolism, shows the opposite trend. Low concentrations of monochloroacetate (MCA), which is known to be neurotoxic, increase as a function of age in the urine of dosed rats. MCA was detectable in plasma only of older animals. Hepatic GSTz1/MAAI-specific activity was inhibited equally by DCA treatment among all age groups, whereas plasma and urinary levels of maleylacetone, a natural substrate for this enzyme, increased with age. We conclude that age is an important variable in the in vivo metabolism and elimination of DCA and that it may account, in part, for the neurotoxicity of this compound in humans and other species.

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, 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 (g/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 g, 2.5 g, 250 g, 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 g/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 g/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.

V.S. DIXIT and A. PANT.2000.An actinomycete isolated from an oil‐contaminated marine environment and identified as Nocardiopsis sp. degraded hydrocarbons and also produced extracellular protease. Conditions for crude oil degradation and simultaneous production of extracellular protease were studied. An alternative approach for bio‐augmented clean‐up of oil spills using a micro‐organism capable of degrading hydrocarbons and recruiting organic nitrogen by producing proteases is reported.

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