Metabolic Effects of Dichloroacetate in Patients with Diabetes Mellitus and Hyperlipoproteinemia

Stacpoole, Peter W.; Moore, G. W. K.; Kornhauser, David M.

doi:10.1056/nejm197803092981002

Cited by 194 publications

(122 citation statements)

References 18 publications

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“…The data presented in Table 1, however, suggest that the ability of DCA to increase expression of E1α and, indeed, of other enzyme components of the PDH complex, may be a more general phenomenon than previously thought. This notion is consistent with clinical studies demonstrating that short-term administration of DCA to healthy subjects [16] or to those with-type 2 diabetes [17] has a blood lactate-lowering effect that persists beyond the residence time of the drug in plasma.…”

Section: Discussionsupporting

confidence: 89%

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

Han

Berendzen

Zhong

et al. 2008

Molecular Genetics and Metabolism

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We determined the ability of self-complementary adeno-associated virus (scAAV) vectors to deliver and express the pyruvate dehy-drogenase E1α subunit gene (PDHA1) in primary cultures of skin fibroblasts from 3 patients with defined mutations in PHDA1 and 3 healthy subjects. Cells were transduced with scAAV vectors containing the cytomegalovirus promoter-driven enhanced green fluorescent protein (EGFP) reporter gene at a vector:cell ratio of 200. Transgene expression was measured 72 h later. The transduction efficiency of scAAV2 and scAAV6 vectors was 3-to 5-fold higher than that of the other serotypes, which were subsequently used to transduce fibroblasts with wild-type PDHA1 cDNA under the control of the chicken beta-action (CBA) promoter at a vector:cell ratio of 1000. Total PDH-specific activity and E1α protein expression were determined 10 days posttransduction. Both vectors increased E1α expression 40-60% in both control and patient cells, and increased PDH activity in two patient cell lines. We also used dichloroacetate (DCA) to maximally activate PDH through dephosphorylation of E1α. Exposure for 24 h to 5 mM DCA increased PDH activity in non-transduced control (mean 37% increase) and PDH deficient (mean 44% increase) cells. Exposure of transduced patient fibroblasts to DCA increased PDH activity up to 90% of the We have proposed that the PDH complex, specifically the E1α subunit, should be considered an important target for gene therapy of mitochondrial energy failure [10]. As proof of concept, we demonstrated that recombinant adeno-associated virus (AAV) could be used to package gene targeting vectors as single-strand molecules carrying the wild-type PDHA1 cDNA, deliver the vector to cultured mammalian cells [11] and partially restore PDH activity in a primary culture of skin fibroblasts from a patient with E1α deficiency [12]. However the efficiency of transgene expression was low (~25% of cells) due to the single-stranded nature of the recombinant vector genome. Moreover, only one AAV serotype was evaluated (AAV2) and the findings were limited to cells from a single patient.Therefore, to optimize the delivery and expression of PDHA1, we employed here doublestranded DNA-containing self-complementary AAV (scAAV) vectors that by-pass the requirement of viral second-strand DNA synthesis. We then investigated the relative transduction efficiency of several scAAV-enhanced green fluorescent protein (EGFP) serotype vectors in both normal and E1α-deficient cultured fibroblasts. Finally, we determined the effectiveness of scAAV-mediated gene transfer alone and combined with DCA to restore PDH activity in defective cells. Materials and methods Cell culture, treatment and plasmidsPrimary cultures of fibroblasts were established from skin biopsies of three healthy subjects and three patients (one male and two females) with PDH E1α deficiency. The patients had the following mutations in the PDHA1 gene: patient 1, c.1163_1166dupAAGT in exon 11; patient 2, c.904C>T in exon 10; and patient 3, c.642G>T in exon...

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Section: Discussionsupporting

confidence: 89%

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

Han

Berendzen

Zhong

et al. 2008

Molecular Genetics and Metabolism

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“…The practical applicability of antilipolysis by nicotinic acid and its derivatives is limited because of undesirable side effects and a marked rebound effect following withdrawal of the drug (Russell and Oliver, 1978). An alternative could be activation of pyruvate dehydrogenase by dichloroacetate-like agents with less toxicity (Stacpoole et al, 1978(Stacpoole et al, , 1979. Studies with pharmacological agents without unwanted side effects are under progress.…”

Section: Discussionmentioning

confidence: 99%

Influence of Myocardial Substrate Utilization on the Oxygen Consumption of the Heart

Kahles

Hellige

Hunneman

et al. 1982

Clinical Cardiology

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Summary:The effect of changing myocardial metabolism from predominantly lipid to predominantly carbohydrate utilization on myocardial oxygen consumption ( MVOz) was studied in 10 closed-chest dogs. Oxygen saving potency df different metabolic interventions was quankified over a wide hernodynamic range by comparing the directly determined MVO2 with the hemodynamic parameter total left ventricular energy demand (El), which correlates closely under control conditions with MV02 (r = 0.98). Stimulation of carbohydrate metabolism by addition of glucose and /3-pyridyl carbinol or by activation of pyruvate dehydrogenase with dichloroacetate (DCA) shifted the cardiac respiratory quotient during @-stimulation from 0.73 to 1 .OO and 0.89, respectively, the nonesterified fatty acid/albumin ratio decreased from 4.0 to 0.5, or remained unchanged with DCA, and MVOz was reduced by 25 and 16%, respectively. Therapeutic approaches aimed at decreasing MV02 by changing substrate utilization are discussed.

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“…Accumulation of lipid droplets (steatosis, lipidosis) was present in some hepatocytes from most groups of mice and in 24.2% of the animals overall (Table 5). The incidence of steatosis was negatively correlated with dose, reflecting the hypolipidemic effects of DCA (Stacpoole et al 1978). There were no incidences of steatosis in six of the eight groups of animals receiving 2.0 and 3.5 g/L DCA, and this was significantly different overall from controls (p = 0.0001, and 0.0094, respectively, see Table 5).…”

Section: Quantificationmentioning

confidence: 94%

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Carter

Deddens

et al. 2003

Environ Health Perspect

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Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.

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Metabolic Effects of Dichloroacetate in Patients with Diabetes Mellitus and Hyperlipoproteinemia

Cited by 194 publications

References 18 publications

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate

Influence of Myocardial Substrate Utilization on the Oxygen Consumption of the Heart

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

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