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Chem Biol Interact. 2014 May 25;215:33-9. doi: 10.1016/j.cbi.2014.02.015. Epub 2014 Mar 13.

Chloride and other anions inhibit dichloroacetate-induced inactivation of human liver GSTZ1 in a haplotype-dependent manner.

Author information

1
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
2
Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, United States.
3
Department of Medicine, University of Florida, Gainesville, FL 32610-0226, United States; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610-0226, United States.
4
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States. Electronic address: mojames@ufl.edu.

Abstract

The in vivo elimination rate of dichloroacetate (DCA), an investigational drug; is determined by the rate of its biotransformation to glyoxylate, catalyzed by glutathione transferase ζ1 (GSTZ1). DCA is a mechanism-based inactivator of GSTZ1, thus elimination of DCA is slowed with repeated dosing. We observed that chloride, a physiologically important anion, attenuated DCA-induced GSTZ1 inactivation in human liver cytosol in a concentration and GSTZ1 haplotype-dependent way. In the absence of chloride, incubation with 0.5mM DCA resulted in inactivation of GSTZ1 with a half-life of 0.4h (samples with the KRT haplotype) to 0.5h (EGT haplotype). At the hepatic physiological chloride concentration, 38mM, samples with the EGT haplotype retained more activity (80%) following a 2-h incubation with 0.5mM DCA than those possessing the KRT haplotype (55%). The chloride concentration that protected 50% of the GSTZ1 activity following 2-h incubation with 0.5mM DCA (EC50) was 15.0±3.1mM (mean±S.D., n=3) for EGT samples and 36.2±2.2mM for KRT samples. Bromide, iodide and sulfite also protected GSTZ1 from inactivation by DCA, however fluoride, sulfate, carbonate, acetate, cyanide did not. Protection by bromide varied by GSTZ1 haplotype: EC50 was 1.3±0.3mM for the EGT haplotype and 5.0±0.60mM for the KRT haplotype. The EC50 values for iodide and sulfite in liver cytosol samples with EGT haplotype were respectively 0.14±0.06mM and 9.6±1.1mM (mean±S.D., n=3). Because the in vivo half-life of DCA is determined by the fraction of active GSTZ1 in the liver, identifying factors that regulate GSTZ1 activity is important in determining appropriate DCA dosing in humans.

KEYWORDS:

Anion protection; Chloride; DCA-induced inactivation; Dichloroacetate; Glutathione transferase zeta

PMID:
24632415
PMCID:
PMC4019600
DOI:
10.1016/j.cbi.2014.02.015
[Indexed for MEDLINE]
Free PMC Article

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