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Intracellular chloride concentration and its impact on dichloroacetate metabolism (1143.2)
Author(s) -
Jahn Stephan,
Zhong Guo,
Smeltz Marci,
RowlandFaux Laura,
Stacpoole Peter,
James Margaret
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1143.2
Subject(s) - intracellular , chemistry , glutathione , metabolism , enzyme , pyruvate dehydrogenase kinase , pharmacology , biochemistry , pyruvate dehydrogenase complex , medicine
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase and an investigational drug used to treat mitochondrial disorders, pulmonary arterial hypertension, and cancer. The enzyme that metabolizes it, glutathione transferase Z1‐1 (GSTZ1‐1), is irreversibly inactivated upon metabolism of DCA. This leads to decreased clearance of subsequent doses and a buildup of the toxic physiological substrates of GSTZ1‐1, maleylacetone and maleylacetoacetate, possibly causing the observed side effect of peripheral neuropathy upon chronic administration. We have observed that the extent of this inactivation is dependent on chloride ion concentration, with high concentrations providing a protective effect. Here, we present data measuring intracellular [Cl‐] in human tissues and the effects that it has on the mechanism of inactivation, adduct formation. These results have important implications in the use of DCA, including predicting patient response, and may provide information to advance the use of DCA in patients in which GSTZ1‐1 inactivation leads to adverse effects. Grant Funding Source : This work was supported by the US Public Health Service RO1 GM099871.