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.

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

“…The GSTZ1 haplotype frequencies in the current study are consistent with previous reports (Blackburn et al, 2001;Shroads et al, 2011). GSTZ1 haplotype had no effect on protein expression or subcellular distribution of the enzyme but had a major impact on enzymatic activity with DCA.…”

“…Consistent with results obtained with the polymorphic variants of recombinant hGSTZ1 (Blackburn et al, 2001), the GSTZ1A allele, paired with or without the GSTZ1C allele, conferred higher DCA-metabolizing activity for a given level of expression in human liver samples. These findings were also consistent with the faster DCA clearance after an initial DCA dose observed in persons carrying the GSTZ1A allele, compared with those who lacked the allele (Shroads et al, 2011). However, the limited number of samples precluded determining whether the effect of the GSTZ1A allele was dominant over or additive to the effect of the GSTZ1C allele.…”

“…Potential contributing factors pertaining to liver quality were carefully examined and precluded. A novel V99M SNP (rs140540096) was recently identified in a KGM/KGT individual with an extraordinarily slow rate of DCA clearance (Shroads et al, 2011). However, none of the individuals with low GSTZ1 function in our study carried this mutation.…”

“…Individuals carrying at least one GSTZ1C (EGT) and/or GSTZ1B (KGT) alleles only were grouped together because of their lack of difference in activity or expression (analysis not shown). GSTZ1A (KRT) and GSTZ1D (EGM) carriers and GSTZ1A/Z1D heterozygotes were grouped separately based on a recent in vivo study indicating low activity for GSTZ1D and GSTZ1A carriers (Shroads et al, 2011) and our current findings of high in vitro activity associated with the GSTZ1A allele.…”

“…Of these, three SNPs at g.5696GϾA (rs7975), g.5726GϾA (rs7972), and g.6772CϾT (rs1046428) have been shown to be functionally important, resulting in five major GSTZ1 haplotypes, i.e., Z1A, Z1B, Z1C, Z1D, and Z1F, with varying allelic frequencies (Table 1). Recently, the influence of GSTZ1 haplotype on DCA pharmacokinetics was examined in healthy adult subjects (Shroads et al, 2011). Individuals that carried at least one allele of Z1A, in general, showed faster clearance of DCA than individuals not carrying this allele after the first DCA dose.…”