Mice Deficient in Glutathione Transferase Zeta/Maleylacetoacetate Isomerase Exhibit a Range of Pathological Changes and Elevated Expression of Alpha, Mu, and Pi Class Glutathione Transferases

Abstract

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. GSTZ1-1 is identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the catabolic pathways for phenylalanine and tyrosine. In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype. Gstz1(-/-) mice do not have demonstrable activity with maleylacetone and alpha-halo acid substrates, and other GSTs do not compensate for the loss of this enzyme. When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney. The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice. GSTZ1-1-deficient mice showed constitutive induction of alpha, mu, and pi class GSTs as well as NAD(P)H:quinone oxidoreductase 1. The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate.

Targeting of two aspects of metabolism in breast cancer treatment

“…Supernatant protein content was measured using BCA Assay Kit (Pierce, Rockford, IL, USA). Proteins (30 mg/sample) were separated via reducing 10% SDS-PAGE and standard western blotting procedures 45 were used to detect proteins of interest with the following primary antibodies: PDK2 (Cat# AP7039b, Abgent, San Diego, CA, USA), b-actin (Abcam), Noxa (OP180, Calbiochem) and Puma (ab9643, Abcam).…”

Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

“…Although these mice seem to survive and breed successfully, they show enlarged liver and kidneys as well as splenic atrophy (Lim et al, 2004). Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney (Lim et al, 2004).…”

“…Because it seemed likely that a complete deficiency of GSTZ1-1/MAAI may have severe metabolic consequences, Gstz1 knockout mice have been developed in two different laboratories (Fernandez-Canon et al, 2002;Lim et al, 2004). Although these mice seem to survive and breed successfully, they show enlarged liver and kidneys as well as splenic atrophy (Lim et al, 2004).…”

MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

“…The cytosolic GSTZ class of GSTs is expressed in many eukaryotic species, including fungi, plants, insects, and mammals (Board et al 1997). Human GSTZ1, which is identical to maleylacetoacetate isomerase, catalyses two distinct reactions: the biotransformation of a range of α-haloacids, including dichloroacetic acid, a drinking water contaminant, and the GSH-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, the penultimate step in the phenylalanine-tyrosine −/− mice display the induction of some of the cytosolic GST isoenzymes, and the constitutive expression of genes that are regulated by antioxidantresponse elements (AREs) and that respond to oxidative stress via the Keap1/Nrf2 signaling pathway, which regulates the expression of numerous detoxifying and antioxidant genes (Lim et al 2004;Lee and Johnson 2004). All of these findings support the view that the lack of GSTZ1 may induce oxidative stress (Blackburn et al 2006).…”