OBJECTIVES: The zeta-class glutathione transferase GSTZ1-1 catalyses the glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate in the tyrosine catabolic pathway and the biotransformation of alpha-halo acids, including dichloroacetic acid (DCA). Genetic polymorphisms in the coding sequence of GSTZ1 result in significant changes in enzyme function, and deficiency of GSTZ1-1 in mice causes induction of a range of Phase-II enzymes. In this study, the potential for polymorphisms in regulatory sequences to alter gene transcription was investigated. METHODS: A total of 10 single-nucleotide polymorphisms (SNP) were identified in African and Australian European subjects in a region extending 1.5-kb upstream of the GSTZ1 start of transcription. These SNPs formed at least 10 haplotypes and only two were shared between the two population samples. The effect of these SNPs on gene expression was evaluated by the transient expression of specific alleles fused to a luciferase reporter gene. RESULTS: Of the 10 SNPs identified, only -1002 G>A and -289 C>T caused significant changes in promoter activity. The -1002 G>A SNP converts a v-Myb site to a S8 homeodomain (Prx2) site, and the -289 C>T SNP abolishes an Egr1 binding site. CONCLUSION: These SNPs may alter GSTZ1 expression, which may alter the pharmacokinetics of DCA, which is used therapeutically for the treatment of lactic acidosis.
OBJECTIVES: The zeta-class glutathione transferase GSTZ1-1 catalyses the glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate in the tyrosine catabolic pathway and the biotransformation of alpha-halo acids, including dichloroacetic acid (DCA). Genetic polymorphisms in the coding sequence of GSTZ1 result in significant changes in enzyme function, and deficiency of GSTZ1-1 in mice causes induction of a range of Phase-II enzymes. In this study, the potential for polymorphisms in regulatory sequences to alter gene transcription was investigated. METHODS: A total of 10 single-nucleotide polymorphisms (SNP) were identified in African and Australian European subjects in a region extending 1.5-kb upstream of the GSTZ1 start of transcription. These SNPs formed at least 10 haplotypes and only two were shared between the two population samples. The effect of these SNPs on gene expression was evaluated by the transient expression of specific alleles fused to a luciferase reporter gene. RESULTS: Of the 10 SNPs identified, only -1002 G>A and -289 C>T caused significant changes in promoter activity. The -1002 G>A SNP converts a v-Myb site to a S8 homeodomain (Prx2) site, and the -289 C>T SNP abolishes an Egr1 binding site. CONCLUSION: These SNPs may alter GSTZ1 expression, which may alter the pharmacokinetics of DCA, which is used therapeutically for the treatment of lactic acidosis.
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