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

Li, Wenjun; James, Margaret O.; McKenzie, Sarah C.; Calcutt, Nigel A.; Liu, Chen; Stacpoole, Peter W.

doi:10.1124/jpet.110.173195

Cited by 38 publications

(63 citation statements)

References 38 publications

(46 reference statements)

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“…We recently reported the presence of GSTZ1 in liver mitochondria (Li et al, 2011b). Examination of GSTZ1 expression in cytosol and mitochondria showed a similar distribution of the enzyme between the two compartments, independent of the allelic differences ( Table 2).…”

Section: Gstz1 Development In Human Liversmentioning

confidence: 98%

“…Rabbit polyclonal anti-human GSTZ1C antibody was produced using the intact recombinant human GSTZ1C as the antigen (Cocalico Biologicals, Reamstown, PA) (Guo et al, 2006). The antiserum was purified using the Pierce Protein A Antibody Purification kit (Thermo Fisher Scientific, Waltham, MA) before use in immunoblotting (Li et al, 2011b). All other chemicals were of American Chemical Society grade or higher and were purchased from commercial suppliers.…”

Section: Chemicals and Reagents The [1-mentioning

confidence: 99%

“…The other 21 postnatal samples were deidentified human livers, of which 14 were obtained from Vanderbilt University (Nashville, TN) and 7 were collected during surgery at Shands Hospital at the University of Florida (Gainesville, FL). Liver cytosol and mitochondria fractions from these samples were prepared exactly as described by Li et al (2011b). The cell nuclear pellet was used to isolate DNA for genotyping (QIAamp DNA Blood Mini kit; QIAGEN, Valencia, CA).…”

Section: Chemicals and Reagents The [1-mentioning

confidence: 99%

“…Originally identified in the cytosol, GSTZ1 is also found in the mitochondria, where it is expressed to a lesser extent (Li et al, 2011b). GSTZ1 has no detectable activity with the prototypical xenobiotic GST substrate 1-chloro-2,4-dinitrobenzene but does recognize ␣-halocarboxylic acids, such as dichloroacetic and 2-chloropropionic acids, as substrates.…”

Section: Introductionmentioning

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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Section: Gstz1 Development In Human Liversmentioning

confidence: 98%

Section: Chemicals and Reagents The [1-mentioning

confidence: 99%

Section: Chemicals and Reagents The [1-mentioning

confidence: 99%

Section: Introductionmentioning

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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“…For instance, specific mitochondrial GST isoforms are able to protect mitochondria from oxidative insults either indirectly by maintaining appropriate levels of GSH or directly by reducing cellular peroxides and reactive aldehydes, such as 4-hydroxynonenal, generated from lipid peroxidation (Raza 2011). The recent discovery that GSTZ1 also localizes in mitochondria (Li et al 2011) leads to assume that GSTZ1 may also contribute to the cellular redox status and then may be relevant to aging and longevity. Interestingly, Starr et al (2008) showed that the GSTZ1 R42G variant affects both telomere length, a biomarker of stress and physical aging, and suggest that this may occur through oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

Cianni

Campa

Tallaro

et al. 2012

AGE

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The pathways that regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to longevity, a two-stage case-control study in two independent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 candidate SNPs identified in stage 1 (π markers 0 0.1) were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p01.1×10 −3 and p01.4×10 −3 , respectively). Interestingly, both genes are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmental and internal stresses.

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Improving culture performance and antibody production in CHO cell culture processes by reducing the Warburg effect

Buchsteiner

Quek

Gray

et al. 2018

Biotech & Bioengineering

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Lactate is one of the key waste metabolites of mammalian cell culture. High lactate levels are caused by high aerobic glycolysis, also known as the Warburg effect, and are usually associated with adverse culture performance. Therefore, reducing lactate accumulation has been an ongoing challenge in the cell culture development to improve growth, productivity, and process robustness. The pyruvate dehydrogenase complex (PDC) plays a crucial role for the fate of pyruvate, as it converts pyruvate to acetyl coenzyme A (acetyl-CoA). The PDC activity can be indirectly increased by inhibiting the PDC inhibitor, pyruvate dehydrogenase kinase, using dichloroacetate (DCA), resulting in less pyruvate being available for lactate formation. Here, Chinese hamster ovary cells were cultivated either with 5 mM DCA or without DCA in various batch and fed-batch bioreactor processes. In all cultures, DCA increased peak viable cell density (VCD), culture length and final antibody titer. The strongest effect was observed in a fed batch with media and glucose feeding in which peak VCD was increased by more than 50%, culture length was extended by more than 3 days, and the final antibody titer increased by more than twofold. In cultures with DCA, lactate production and glucose consumption during exponential growth were on average reduced by approximately 40% and 35%, respectively. Metabolic flux analysis showed reduced glycolytic fluxes, whereas fluxes in the tricarboxylic acid (TCA) cycle were not affected, suggesting that cultures with DCA use glucose more efficiently. In a proteomics analysis, only few proteins were identified as being differentially expressed, indicating that DCA acts on a posttranslational level. Antibody quality in terms of aggregation, charge variant, and glycosylation pattern was unaffected. Subsequent bioreactor experiments with sodium lactate and sodium chloride feeding indicated that lower osmolality, rather than lower lactate concentration itself, improved culture performance in DCA cultures. In conclusion, the addition of DCA to the cell culture improved culture performance and increased antibody titers without any disadvantages for cell-specific productivity or antibody quality.

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

Cited by 38 publications

References 38 publications

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

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

MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

Improving culture performance and antibody production in CHO cell culture processes by reducing the Warburg effect

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