Disease relevance of Gstz1

• When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy [1].
• Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity [2].
• GSTZ1-1 is inactivated by dichloroacetic acid (DCA), which is used for the clinical management of congenital lactic acidosis and is a drinking-water contaminant [3].

High impact information on Gstz1

• Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products [4].
• A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage [5].
• Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism [5].
• There are well-described human diseases associated with deficiencies of all enzymes in this pathway except for maleylacetoacetate isomerase (MAAI), which converts maleylacetoacetate (MAA) to fumarylacetoacetate (FAA) [5].
• This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice [5].

Biological context of Gstz1

• In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype [1].
• It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1(-/-) mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress [2].
• Therefore, no alternative pathways for DCA clearance appear to exist in mice other than by MAAI-mediated biotransformation [6].
• We also investigated the pharmacokinetics of DCA in the recently developed MAAI knockout (MAAI-KO) mouse [6].
• Expression of GSTzeta/MAAI mRNA and protein was induced during the terminal phase of adipogenesis in 3T3-L1 preadipocytes [7].

Anatomical context of Gstz1

• These data suggest a role for GSTzeta/MAAI in mature adipocytes that may be responsive to the thiazolidinedione class of insulin sensitizing PPARgamma ligands [7].
• Ectopic expression of PPARgamma2 in NIH-3T3 fibroblasts exposed to insulin and troglitazone-induced perilipin production, but was incapable of activating GSTzeta/MAAI unless C/EBPalpha was also expressed [7].

Associations of Gstz1 with chemical compounds

• Gstz1(-/-) mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice [2].
• MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy [5].
• Glutathione transferase zeta (GSTZ1-1) is the major enzyme that catalyzes the metabolism of alpha-halo acids such as dichloroacetic acid, a carcinogenic contaminant of chlorinated water [1].
• DCA is biotransformed to glyoxylate by maleylacetoacetate isomerase (MAAI) [6].

Analytical, diagnostic and therapeutic context of Gstz1

• Induction of GST subunits was detected in the liver of Gstz1(-/-) mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins [2].
• Mass spectrometric sequencing of the protein following its purification by HPLC and preparative 2D gel electrophoresis identified it as glutathione S-transferase zeta/maleylacetoacetate isomerase (GSTzeta/MAAI) [7].

References