Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase ζ1
作者： Wenjun Li , Margaret O. James , Sarah C. McKenzie , Nigel A. Calcutt , Chen Liu
关键词: Dichloroacetic acid 、 Enzyme 、 GSTZ1 、 Glutathione 、 Biology 、 Mitochondrion 、 Biochemistry 、 Cytosol 、 Mitochondrial matrix 、 Pyruvate dehydrogenase kinase
摘要: Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition glutathione transferase ζ1 (GSTZ1), cytosolic enzyme that converts to glyoxylate. known be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis mitochondrion was also site biotransformation. Immunoreactive GSTZ1 detected liver mitochondria from humans rats, identity confirmed liquid chromatography/tandem mass spectrometry analysis tryptic peptides. Study rat submitochondrial fractions revealed localized mitochondrial matrix. The specific activity GSTZ1-catalyzed dechlorination 2.5- 3-fold higher cytosol than whole directly proportional protein expression two compartments. Rat had 2.5-fold AppKm for GSTZ1, whereas values were identical. Rats administered at dose 500 mg/kg/day 8 weeks showed hepatic ∼10% control levels both mitochondria. conclude novel biotransformation catalyzed colocalized
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