Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate

Abstract

Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1)/maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-¹³C-DCA when it was administered at either environmentally (µg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA's adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.

Figures

Figure 1

Bifunctionality of glutathione transferase zeta (A)/maleylacetoacetate isomerase (B) (GSTz1/MAAI). See text for details.

Figure 2

Glutathione transferase zeta/maleylacetoacetate isomerase (GSTz1/MAAI) haplotype frequencies in 588 participants.

Figure 3

Sequence chromatogram of mutation G259A (NM_145870) in exon 5 of GSTz1/MAAI.

Figure 4

Plasma kinetics and biotransformation of dichloroacetate (DCA; 25 mg/kg/d). All panels show plasma 13C-DCA concentrations over 24 hours following 1 and 5 days, respectively, of oral administration of 25 mg/kg dose of 1,2-13C-DCA. Also shown is the time course of 13CO2 accumulation in exhaled breath as a percentage of the administered dose 13C-DCA. Panels A and B show representative data from participant 1 (EGT/EGT) in Table I, a fast metabolizer of DCA. Panels C and D show data from participant 12 (KGM/KGT), a slow metabolizer of DCA.

Figure 5

Structural variance in glutathione transferase zeta/maleylacetoacetate isomerase (GSTz1/MAAI). Panel A shows homodimeric GSTz1/MAAI as a ribbon diagram in which each subunit is colored gold or blue. Polymorphic side chains are depicted as spheres colored yellow for carbon, blue for nitrogen, and red for oxygen. Panel B shows the crystal structure of GSTz1/MAAI and model containing the Val99Met mutation. GSTz1/MAAI is represented as a ribbon diagram. Covalent bonds of side chains in close proximity to position 99 (within 4 Å) of GSTz1/MAAI are shown as sticks colored as in A. The Met 99 residue is colored magenta for carbon and yellow for sulfur.