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Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.

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 ?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 ?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.

SUBMITTER: Li W

PROVIDER: S-EPMC3014303 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.

Li Wenjun W James Margaret O MO McKenzie Sarah C SC Calcutt Nigel A NA Liu Chen C Stacpoole Peter W PW

The Journal of pharmacology and experimental therapeutics 20100930 1

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 ...[more]

PMID: 20884751

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Project description:Dichloroacetate (DCA) has potential for treating mitochondrial disorders and cancer by activating the mitochondrial pyruvate dehydrogenase complex. Repeated dosing of DCA results in reduced drug clearance due to inactivation of glutathione transferase ζ1 (GSTZ1), its metabolizing enzyme. We investigated the time-course of inactivation of GSTZ1 in hepatic cytosol and mitochondria after one oral dose of 100 mg/kg DCA to female Sprague-Dawley rats aged 4 weeks (young) and 52 weeks (adult) as models for children and adults, respectively. GSTZ1 activity with both DCA and an endogenous substrate, maleylacetone (MA), as well as GSTZ1 protein expression were rapidly reduced in cytosol from both ages following DCA treatment. In mitochondria, loss of GSTZ1 protein and activity with DCA were even more rapid. The cytosolic in vivo half-lives of the loss of GSTZ1 activity with DCA were 1.05 ± 0.03 and 0.82 ± 0.02 h (mean ± S.D., n = 6) for young and adult rats, respectively, with inactivation significantly more rapid in adult rats, p < 0.001. The mitochondrial inactivation half-lives were similar in young (0.57 ± 0.02 h) and adult rats (0.54 ± 0.02 h) and were significantly (p < 0.0001) shorter than cytosolic inactivation half-lives. By 24 h after DCA administration, activity and expression remained at 10% or less than control values. The in vitro GSTZ1 inactivation half-lives following incubation with 2 mM DCA in the presence of physiological chloride (Cl-) concentrations (cytosol = 44 mM, mitochondria = 1-2 mM) exhibited marked differences between subcellular fractions, being 3 times longer in the cytosol than in the mitochondria, regardless of age, suggesting that the lower Cl- concentration in mitochondria explained the faster degradation of GSTZ1. These results demonstrate for the first time that rat mitochondrial GSTZ1 is more readily inactivated by DCA than cytosolic GSTZ1, and cytosolic GSTZ1 is inactivated more rapidly in adult than young rats.

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Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.

Publications

Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1.

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