Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

Shroads, Albert L.; Xu, Guowang; Dixit, Vaishali; Liu, Huiping; James, Margaret O.; Stacpoole, Peter W.

doi:10.1124/jpet.107.134593

Cited by 57 publications

(87 citation statements)

References 20 publications

(31 reference statements)

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“…DCA is already established in clinical practice. The Cmax value of DCA in adults following 6 months of continuous treatment (oral doses of 25 mg/kg/day) was 53±18 µg/ml (0.35±0.12 mM) (18). Patients were safely treated chronically with DCA at the maximum dose of 50 mg/kg/day (19).…”

Section: Discussionmentioning

confidence: 99%

Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors

Ishiguro

et al. 2012

Oncology Letters

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Abstract. It has been reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth). Furthermore, omeprazole (OMP) is a well-known agent that enhances the effects of anticancer drugs. The aim of this study was to find clinically-used drugs that enhance the effects of DCA. The combination of DCA and OMP exhibited a more potent antitumor activity than DCA alone in HT1080 fibrosarcoma cells and RKO colon cancer cells, while the drugs did not affect the proliferation of WI-38 human fibroblasts. The inhibitory effect of DCA combined with OMP was reversed with vitamin E and Z-VAD-FMK; therefore conventional caspase-dependent cell growth inhibition through superoxide production was suggested as the mechanism for inhibition. The combination of these drugs also had an effect on HT1080 fibrosarcoma cells inoculated into mice. Since OMP and DCA may be administered orally and have been used clinically for several years without major side effects, we believe that this combination therapy could be readily translated to treat malignant tumors. IntroductionWarburg first observed that even in the presence of sufficient oxygen, cancer cells prefer to metabolize glucose and produce lactic acid (1-4). The concomitant increase in glucose uptake may be exploited clinically for the detection of most solid malignant tumors by fluorodeoxyglucose positron emission tomography (FDG-PET). One possible reason for cancers adopting this less efficient pathway for producing adenosine triphosphate (ATP) compared with oxidative phosphorylation is its advantage for survival and proliferation in the unique hypoxic tumor environment (5). This preference for anaerobic respiration is also considered to be the reason for the resistance cancer cells exhibit to anticancer drugs which induce apoptosis via the mitochondrial pathway. Bonnet et al have reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth (3,4,(6)(7)(8). DCA increases the flux of pyruvate into the mitochondria by inhibiting the pyruvate dehydrogenase kinase and promotes glucose oxidation over glycolysis. As a result, DCA decreases the production of lactic acid by the tumor and increases the intracellular pH. DCA induces apoptosis via two pathways, one in the mitochondria, where depolarization and superoxide (SOD) production activates mitochondria-dependent apoptosis, and the other at the plasmalemmal level, where activation/upregulation of Kv1.5 channels decreases the (K + )i, activating caspases (6). DCA is a promising anticancer drug due to the convenience of its oral administration, low cost, few side effects and long experience of clinical use (7,8). Although it appeared to be a promising treatment for malignant tumors, its effect is limited in an ongoing report of clinical trials. Therefore, we aimed to find clinically-used drugs that enhance the effects of DCA....

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Section: Discussionmentioning

confidence: 99%

Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors

Ishiguro

et al. 2012

Oncology Letters

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“…Human studies showed no differences in single-dose DCA pharmacokinetics between children younger than 7 years and adults (mean age, 24 years) (Shroads et al, 2008(Shroads et al, , 2011. The initial elimination half-life was 2.5 Ϯ 0.4 h (mean Ϯ S.D.)…”

Section: Et Almentioning

confidence: 93%

“…In contrast, children with heterogeneous causes of congenital lactic acidosis showed no worsening of hepatotoxicity or neurotoxicity even after chronic DCA treatment . Examination of DCA plasma kinetics revealed similar clearance and other indices between children (age, 2.2-7.1 years at entry; mean age Ϯ S.D., 5.2 Ϯ 1.8; n ϭ 5) and older individuals (age, 14.0 -33.9 at entry; mean age Ϯ S.D., 23.6 Ϯ 10.0; n ϭ 4) after their initial doses, whereas a striking age-dependent decrease in DCA clearance was observed at the end of 6 months of treatment (Shroads et al, 2008).…”

Section: Introductionmentioning

confidence: 95%

“…Therefore, it does not explain the differences in DCA clearance between children and adults upon chronic treatment (Shroads et al, 2008), or between individuals of GSTZ1A/Z1A and GSTZ1A/Z1D haplotypes relative to other haplotypes after repeated doses (Shroads et al, 2011). Our preliminary studies showed haplotype-dependent differences in DCA-induced inactivation of GSTZ1, an effect that was further modulated by chloride and other anions (Li et al, 2011a;W.…”

Section: Et Almentioning

confidence: 99%

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Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Gu²,

James³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Glutathione transferase 1 (GSTZ1), also known as maleylacetoacetate isomerase, catalyzes the penultimate step of tyrosine catabolism and metabolizes several ␣-halocarboxylic acids, including dichloroacetic acid (DCA), an investigational drug used for lactic acidosis and, recently, solid tumors. Age-related differences have been suggested in DCA pharmacotoxicology, but no information is available on GSTZ1 ontogeny in humans. Here, we investigated the cytosolic GSTZ1 developmental expression pattern and the influence of haplotype on GSTZ1 activity with DCA by using human livers from donors between 10 weeks gestation and 74 years. GSTZ1 expression was very low in fetal livers (<2 pmol of GSTZ1/mg cytosol). The expression began to increase after birth in an age-dependent manner until age 7 years. GSTZ1 was then sustained at stable, yet variable, levels (median, 20.0 pmol/mg cytosol; range, 4.8-47.3 pmol/mg cytosol) until age 74 years. GSTZ1 activity with DCA was strongly associated with haplotype and expression level. Samples homozygous or heterozygous for GSTZ1A exhibited ϳ3-fold higher DCA dechlorinating activity than samples carrying other alleles at a given level of expression. The correlations (r 2 ) between activity and expression were 0.90 and 0.68, respectively, for GSTZ1A carriers (n ‫؍‬ 11) and noncarriers (n ‫؍‬ 61). GSTZ1 is expressed in mitochondria in addition to cytosol. The GSTZ1A allele exhibited similar effects in the mitochondrial fraction by conferring a higher activity with DCA. In summary, we report a neonatal onset and an age-related increase in GSTZ1 protein expression during human liver development. Haplotype influenced GSTZ1 activity with DCA but not protein expression.

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“…GSTZ1 is the only GST known to metabolize DCA. A trace amount of DCA can also be reductively dechlorinated to monochloroacetate in the blood (Shroads et al, 2008). In vivo exposure to DCA causes a dose-and duration-dependent reduction in hepatic GSTZ1 expression and activity (Cornett et al, 1999;Ammini et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Li¹,

James²,

McKenzie³

et al. 2010

J Pharmacol Exp Ther

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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 1 (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 ϳ10% 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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Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

Cited by 57 publications

References 20 publications

Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors

Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors

Prenatal and Postnatal Expression of Glutathione Transferase ζ 1 in Human Liver and the Roles of Haplotype and Subject Age in Determining Activity with Dichloroacetate

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

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