Abstract

Glutathione transferase zeta 1 (GSTZ1) is a member of the GST superfamily and is localized in cytosol and, to a lesser extent, in mitochondria. It functions as maleylacetoacetate isomerase as well as the metabolizing enzyme of α-halocarboxylic acids, including dichloroacetic acid (DCA), an investigational drug used for lactic acidosis and recently solid tumors. Here, we investigated the cytosolic GSTZ1 developmental expression pattern and the influence of haplotype on GSTZ1 activity with DCA by using human livers from donors who succumbed at 10 weeks gestation to 74 years. GSTZ1 expression was very low in fetal livers (<2 pmol GSTZ1/mg cytosol). The expression began to increase after birth in an age-dependent manner until age 7 years. GSTZ1 was then sustained at stable yet variable levels (median = 20.0 pmol/mg cytosol, range: 4.8 - 47.3 pmol/mg cytosol) till age 74 years. GSTZ1 activity with DCA was strongly associated with haplotype and expression level. Samples homo- or heterozygous for GSTZ1A exhibited ~3-fold higher DCA dechlorinating activity than samples carrying other alleles at a given level of expression. The correlations (R²) between activity and expression were 0.90 and 0.68, respectively, for GSTZ1A carriers (n=11) and noncarriers (n=61). The GSTZ1A allele also conferred a higher activity with DCA with enzyme isolated from the mitochondrial fraction. In summary, we report a neonatal onset and an age-related increase in GSTZ1 protein expression during human liver development. Haplotype influenced GSTZ1 activity with DCA but not protein expression.