Cited by 145Metabolism and Genetic DisordersBiochemical Acid Research StudiesMitochondrial Function and Pathology

Role of dichloroacetate in the treatment of genetic mitochondrial diseases

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Stacpoole, Peter W., Kurtz, Tracie L., Han, Zongchao, Langaee, Taimour·2008·Advanced Drug Delivery Reviews

Abstract

Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition.

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Crossref · 10.1016/j.addr.2008.02.014

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  • Dichloroacetate increases PDC activity by decreasing E1α phosphorylation and turnover.

    “which stimulates PDC activity by reducing the phosphorylation and turnover of E1α (Morten et al., 1999; Stacpoole et al., 2008).”

    From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Stacpoole et al., 2008

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Authors
Stacpoole, P. W., Kurtz, T. L., Han, Z., & Langaee, T.
Affiliations
  • University of Florida Health (US)
  • University of Florida (US)
Corresponding author
Stacpoole, Peter W.
Venue
Advanced Drug Delivery Reviews
Publisher
Elsevier BV
Published
2008-10
Volume
60
Issue
13-14
Pages
1478-1487
ISSN
0169-409X (ISSN-L)
OpenAlex
W2040632966
Cited by
145
References
44
Citations by year
2026: 3 · 2025: 8 · 2024: 12 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 5
FWCI
1.20
Type
journal article
Language
en
Open access
Locations
  • Advanced Drug Delivery Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
Funders
  • National Institutes of Health (5r01es014617-05)
  • National Institute of Environmental Health Sciences (R01-ES014617, ES007355, R01ES007355, ES-014617)
  • National Center for Research Resources (M01RR000032, M01RR000082)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
dichloroacetate, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase complex, enzyme polymorphism, drug metabolism, drug toxicity, age-related drug response, gene therapy, oral administration
MeSH terms
Adult, Aging, Child, Dichloroacetic Acid, Glutathione Transferase, Haplotypes, Humans, Isoenzymes, Pyruvate Dehydrogenase Complex, Pyruvate Dehydrogenase Complex Deficiency Disease, Randomized Controlled Trials as Topic, cis-trans-Isomerases, Polymorphism, Single Nucleotide, Mitochondrial Diseases

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