Abstract
Dichloroacetate (DCA) is an investigational drug for certain metabolic diseases. It is biotransformed principally by the ζ-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.
Footnotes
-
This study was supported by National Institutes of Health Grants ES-007355, ES-07375, ES-014617, and M01 RR-000082; some of this work was presented previously in abstract form: Stacpoole PW, Shroads AL, Felitsyn NM, Notterpek L, Calcutt NA (2006) Mechanism of age dependence of dichloroacetate-induced peripheral neuropathy. United Mitochondrial Disease Foundation; 2006 Jun 14–18; Atlanta, GA. United Mitochondrial Disease Foundation, Pittsburgh, PA.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.134593.
-
ABBREVIATIONS: DCA, dichloroacetate; GSTz1, ζ-1 family isoform of glutathione transferase; MAAI, maleylacetoacetate isomerase; MA, maleylacetone; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; GC-MS, gas chromatography-mass spectrometry; MCA, monochloroacetate; AUC, area under the plasma-concentration time curve; CL, total body clearance; LOD, limit of detection.
- Received November 21, 2007.
- Accepted December 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|