ArticleThe Journal of pharmacology and experimental therapeutics2011
Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.
Article in The Journal of pharmacology and experimental therapeutics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children.Journal of clinical pharmacology · 2018Trial
- Identification of a Novel Target Implicated in Chronic Obstructive Sleep Apnea-Related Atrial Fibrillation by Integrative Analysis of Transcriptome and Proteome.Journal of inflammation research · 2023Article
- Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases.International journal of nanomedicine · 2023Review
- An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.Frontiers in physiology · 2022Article
- Effects of Multiple Doses of Dichloroacetate on GSTZ1 Expression and Activity in Liver and Extrahepatic Tissues of Young and Adult Rats.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Exposure of Rats to Multiple Oral Doses of Dichloroacetate Results in Upregulation of Hepatic Glutathione Transferases and NAD(P)H Dehydrogenase [Quinone] 1.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Mitochondrial Glutathione Transferase Zeta 1 Is Inactivated More Rapidly by Dichloroacetate than the Cytosolic Enzyme in Adult and Juvenile Rat Liver.Chemical research in toxicology · 2019Article
- Review
- Gender-Related Effect of Sodium Dichloroacetate on the Number of Hassall's Corpuscles and RNA NKCC1 Expression in Rat Thymus.BioMed research international · 2019Article
- Age-Related Changes in Expression and Activity of Human Hepatic Mitochondrial Glutathione Transferase Zeta1.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Regulation of dichloroacetate biotransformation in rat liver and extrahepatic tissues by GSTZ1 expression and chloride concentration.Biochemical pharmacology · 2018Article
- Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1.Pharmacology & therapeutics · 2017Review
- GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate.Biochimica et biophysica acta · 2016Article
- Pharmacogenetic considerations with dichloroacetate dosing.Pharmacogenomics · 2016Review
- Fatal Liver and Bone Marrow Toxicity by Combination Treatment of Dichloroacetate and Artesunate in a Glioblastoma Multiforme Patient: Case Report and Review of the Literature.Frontiers in oncology · 2016Article
- Chloride concentrations in human hepatic cytosol and mitochondria are a function of age.Biochemical and biophysical research communications · 2015Article
- Dichloroacetate Decreases Cell Health and Activates Oxidative Stress Defense Pathways in Rat Alveolar Type II Pneumocytes.BioMed research international · 2015Article
- Chloride and other anions inhibit dichloroacetate-induced inactivation of human liver GSTZ1 in a haplotype-dependent manner.Chemico-biological interactions · 2014Article
- Preliminary X-ray crystallographic analysis of glutathione transferase zeta 1 (GSTZ1a-1a).Acta crystallographica. Section F, Structural biology communications · 2014Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase ζ1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5- to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher (App)K(m) for glutathione than cytosolic GSTZ1, whereas the (App)K(m) values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of ∼10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.
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