Inhibition of Glutathione S-Transferase ζ and Tyrosine Metabolism by Dichloroacetate: A Potential Unifying Mechanism for Its Altered Biotransformation and Toxicity

Cornett, Rachel; James, Margaret O.; Henderson, George N.; Cheung, Jang; Shroads, Albert L.; Stacpoole, Peter W.

doi:10.1006/bbrc.1999.1287

Cited by 73 publications

(83 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The studies of MAAI knockout mice reported here show that the MAAI gene is not an essential gene for the catabolism of phenylalanine and tyrosine in mice under laboratory conditions. It has also has been shown by others that MAAI is able to catalyze the conversion of DCA to glyoxylate (7,38). Therefore, MAAI has been proposed as a precursor in the evolution of some dehalogenases (1).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that DCA, a compound which is in clinical trials for the treatment of lactic acidosis, is detoxified by MAAI (7,38). It is also known that DCA inactivates MAAI and hence can induce hepatic MAAI deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…MAAI was also isolated independently as GSH transferase zeta (GSTZ1) (6). In addition to its function in tyrosine degradation, MAAI/ GSTZ1 therefore is involved in detoxification of xenobiotic compounds such as dichloroacetic acid (DCA) (7,39).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism

Fernández-Cañón¹,

Baetscher²,

Finegold

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

In mammals, the catabolic pathway of phenylalanine and tyrosine is found in liver (hepatocytes) and kidney (proximal tubular cells). 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). MAAI is also known as glutathione transferase zeta (GSTZ1). Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene. MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy. This observation suggested that either accumulating MAA is not toxic or an alternate pathway for MAA metabolism exists. 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. However, evidence for a partial bypass of MAAI activity was also found. Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI. Double mutants showed predominant renal injury, indicating that this organ is the primary target for the accumulated compound(s) resulting from MAAI deficiency. A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism

Fernández-Cañón¹,

Baetscher²,

Finegold

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Moreover, GSTZ1-1 activities and immunoreactive GSTZ1-1 protein concentrations are reduced in hepatic cytosolic fractions from rats given DCA for 5 days (Anderson et al, 1999). The DCA-induced inactivation of GSTZ1-1 perturbs tyrosine metabolism in rats (Cornett et al, 1999), and these perturbations may be associated with the multiorgan toxicity of DCA. The multiorgan toxicity of DCA also indicates that GSTZ1-1 may be expressed in different organs.…”

Section: Introductionmentioning

confidence: 97%

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

Lantum

Baggs²,

Krenitsky³

et al. 2002

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of a range of ␣-haloacids, including dichloroacetic acid (DCA), and the penultimate step in the tyrosine degradation pathway. DCA is a rodent carcinogen and a common drinking water contaminant. DCA also causes multiorgan toxicity in rodents and dogs. The objective of this study was to determine the expression and activities of GSTZ1-1 in rat tissues with maleylacetone and chlorofluoroacetic acid as substrates. GSTZ1-1 protein was detected in most tissues by immunoblot analysis after immunoprecipitation of GSTZ1-1 and by immunohistochemical analysis; intense staining was observed in the liver, testis, and prostate; moderate staining was observed in the brain, heart, pancreatic islets, adrenal medulla, and the epithelial lining of the gastrointestinal tract, airways, and bladder; and sparse staining was observed in the renal juxtaglomerular regions, skeletal muscle, and peripheral nerve tissue. These patterns of expression corresponded to GSTZ1-1 activities in the different tissues with maleylacetone and chlorofluoroacetic acid as substrates. Specific activities ranged from 258 ؎ 17 (liver) to 1.1 ؎ 0.4 (muscle) nmol/min/mg of protein with maleylacetone as substrate and from 4.6 ؎ 0.89 (liver) to 0.09 ؎ 0.01 (kidney) nmol/min/mg of protein with chlorofluoroacetic acid as substrate. Rats given DCA had reduced amounts of immunoreactive GSTZ1-1 protein and activities of GSTZ1-1 in most tissues, especially in the liver. These findings indicate that the DCA-induced inactivation of GSTZ1-1 in different tissues may result in multiorgan disorders that may be associated with perturbed tyrosine metabolism.Glutathione transferases (GST 1 ) are a multigene family of phase II drug-metabolizing enzymes that catalyze the conjugation of glutathione with a range of endogenous and exogenous substrates (Armstrong, 1997;Salinas and Wong, 1999). Soluble and membrane-bound GSTs are expressed in many tissues, and soluble GSTs constitute 1 to 5% of total cytosolic protein (Morgenstern et al., 1984;Sundberg et al., 1993;Rowe et al., 1997). Activities with model substrates and the subcellular localization of GSTA, GSTM, GSTP, GSTT, and GSTO class GSTs and of microsomal GST1 have been previously characterized (Meyer et al., 1991;Hiratsuka et al., 1994;Mannervik and Widersten, 1995;Armstrong, 1997;Otieno et al., 1997;Yin et al., 2001).The expression of GSTs is regulated pre-and post-translationally in a tissue-specific manner resulting in protein products that differ quantitatively in different tissues (Tu et al., 1983;Rozell et al., 1993;Rowe et al., 1997). Testes express the highest amount of total GST protein per milligram cytosolic protein followed by the liver, brain, pancreas, adrenals, heart, and lung (DePierre and Morgenstern, 1983;Listowsky et al., 1998). Major GST-expressing tissues are the principal sites for drug and chemical metabolism indicative of the role of GSTs in the biotransformation of xenobiotics (Pabst et al., 1973;Armstrong, 1997). Studies...

show abstract

“…Liver expresses the highest amount of total GSTz1-1 protein per milligram of cytosolic protein, followed by brain and lung. DCA is a mechanism-based inhibitor of GSTz1-1 (Anderson et al, 1999(Anderson et al, , 2002Tzeng et al, 2000) at clinically relevant doses and increases the urinary excretion of maleylacetone (MA), an endogenous substrate for the isomerase (Cornett et al, 1999;.…”

mentioning

confidence: 99%

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Xu¹,

Dixit²,

Liu³

et al. 2005

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:Dichloroacetate (DCA) is an investigational drug for certain metabolic disorders, a by-product of water chlorination and a metabolite of certain industrial solvents and drugs. DCA is biotransformed to glyoxylate by glutathione S-transferase zeta (GSTz1-1), which is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/day) decrease the activity and expression of GSTz1-1, which alters tyrosine metabolism and may cause hepatic and neurological toxicity. The effect of environmental DCA doses (g/kg/day) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following subchronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 g, 2.5 g, 250 g, or 50 mg DCA/kg/day in drinking water for up to 12 weeks. Recovery was followed after the 8-week exposure. GSTz specific activity and protein expression (Western immunoblotting) were decreased in a dose-dependent manner by 12 weeks of exposure. Enzyme activity and expression decreased 95% after a 1-week administration of high-dose DCA. Eight weeks after cessation of high-dose DCA, GSTz activity had returned to control levels. At the 2.5 or 250 g/kg/day doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60 to 75 g/kg/24 h in animals exposed to 50 mg/kg/day DCA. The liver/body weight ratio increased in the high-dose group after 8 weeks of DCA. These studies demonstrate that short-term administration of DCA inhibits rat liver GSTz across the wide concentration range to which humans are exposed.

show abstract

Inhibition of Glutathione S-Transferase ζ and Tyrosine Metabolism by Dichloroacetate: A Potential Unifying Mechanism for Its Altered Biotransformation and Toxicity

Cited by 73 publications

References 14 publications

Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism

Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism

Immunohistochemical Localization and Activity of Glutathione Transferase Zeta (GSTZ1–1) in Rat Tissues

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Contact Info

Product

Resources

About