Age-Related Changes in Expression and Activity of Human Hepatic Mitochondrial Glutathione Transferase Zeta1

Zhong, Guo; James, Margaret O.; Smeltz, Marci; Jahn, Stephan C.; Langaee, Taimour; Simpson, Pippa; Stacpoole, Peter W.

doi:10.1124/dmd.118.081810

Cited by 9 publications

(14 citation statements)

References 55 publications

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“…Considering the total expression of GSTZ1 in rat liver, 86% is in cytosol and 14% is in mitochondria. The properties of the hepatic mitochondrial enzyme are not identical to those of the cytosolic form, in that the apparent K m for GSH is higher in mitochondria than in cytosol in the rat (Li, et al, 2011) and human (Zhong, et al, 2014b). To date, however, no protein sequence differences have been identified in GSTZ1 isolated from each location in either rat or human (Zhong and James, unpublished observations), and the molecular basis for these differences in enzyme kinetics is not yet known.…”

Section: The Physiological Role and Properties Of Gstz1mentioning

confidence: 98%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

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110

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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Section: The Physiological Role and Properties Of Gstz1mentioning

confidence: 98%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

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110

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“…Previous studies by our laboratory and others have failed to identify any transcriptional regulators or posttranslational modifications that would be expected to modulate stability of GTSZ1 (Ammini et al, 2003;Zhong et al, 2018). Additionally, there was no correlation between GSTZ1 mRNA levels and protein expression (Langaee et al, 2015).…”

Section: Introductionmentioning

confidence: 67%

“…It is also the sole enzyme responsible for the metabolism of the experimental drug dichloroacetate (DCA), which has shown promise in the treatment of mitochondrial disorders, cancer, and pulmonary hypertension, among other diseases. Although humans are born with little to no hepatic GSTZ1 expression, its levels undergo an increase shortly after birth before plateauing around age 7 years in cytosol and 21 years in mitochondria (Li et al, 2012;Zhong et al, 2018). This age-related expression is clinically relevant, as dosage with DCA must be appropriate for the extent of GSTZ1-mediated metabolism [reviewed in James et al (2017)].…”

Section: Introductionmentioning

confidence: 99%

Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes

Jahn¹,

Weaver²,

Renne³

et al. 2020

Drug Metab Dispos

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Previous work has shown that hepatic levels of human glutathione transferase zeta 1 (GSTZ1) protein, involved in tyrosine catabolism and responsible for metabolism of the investigational drug dichloroacetate, increase in cytosol after birth before reaching a plateau around age 7. However, the mechanism regulating this change of expression is still unknown, and previous studies showed that GSTZ1 mRNA levels did not correlate with GSTZ1 protein expression. In this study, we addressed the hypothesis that microRNAs (miRNAs) could regulate expression of GSTZ1. We obtained liver samples from donors aged less than 1 year or older than 13 years and isolated total RNA for use in a microarray to identify miRNAs that were downregulated in the livers of adults compared with children. From a total of 2578 human miRNAs tested, 63 miRNAs were more than 2-fold down-regulated in adults, of which miR-376c-3p was predicted to bind to the 39 untranslated region of GSTZ1 mRNA. There was an inverse correlation of miR-376c-3p and GSTZ1 protein expression in the liver samples. Using cell culture, we confirmed that miR-376c-3p could downregulate GSTZ1 protein expression. Our findings suggest that miR-376c-3p prevents production of GSTZ1 through inhibition of translation. These experiments further our understanding of GSTZ1 regulation. Furthermore, our array results provide a database resource for future studies on mechanisms regulating human hepatic developmental expression. SIGNIFICANCE STATEMENTHepatic glutathione transferase zeta 1 (GSTZ1) is responsible for metabolism of the tyrosine catabolite maleylacetoacetate as well as the investigational drug dichloroacetate. Through examination of microRNA (miRNA) expression in liver from infants and adults and studies in cells, we showed that expression of GSTZ1 is controlled by miRNA. This finding has application to the dosing regimen of the drug dichloroacetate. The miRNA expression profiles are provided and will prove useful for future studies of drug-metabolizing enzymes in infants and adults.

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“…Thus, mitochondrial-specific SOD2 is acknowledged as the primary enzymic antioxidant against oxidative damage within mitochondria and the prevention of cellular senescence [ 19 , 24 , 32 , 44 , 58 ]. Increased GSTZ1 expression, especially mitochondrial GSTZ1, has also been strongly associated with decreased human aging and prolonged longevity, partly due to reduced telomere shortening [ 64 , 65 ]. Furthermore, GSTZ1 −/− mice possess alterations in mitochondrial ultrastructure, size, and activity, confirming the protective roles of GSTZ1 in mitochondria [ 61 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

Differential SOD2 and GSTZ1 profiles contribute to contrasting dental pulp stem cell susceptibilities to oxidative damage and premature senescence

et al. 2021

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Background Dental pulp stem cells (DPSCs) are increasingly being advocated as viable cell sources for regenerative medicine-based therapies. However, significant heterogeneity in DPSC expansion and multi-potency capabilities are well-established, attributed to contrasting telomere profiles and susceptibilities to replicative senescence. As DPSCs possess negligible human telomerase (hTERT) expression, we examined whether intrinsic differences in the susceptibilities of DPSC sub-populations to oxidative stress-induced biomolecular damage and premature senescence further contributed to this heterogeneity, via differential enzymic antioxidant capabilities between DPSCs. Methods DPSCs were isolated from human third molars by differential fibronectin adhesion, and positive mesenchymal (CD73/CD90/CD105) and negative hematopoietic (CD45) stem cell marker expression confirmed. Isolated sub-populations were expanded in H2O2 (0–200 μM) and established as high or low proliferative DPSCs, based on population doublings (PDs) and senescence (telomere lengths, SA-β-galactosidase, p53/p16INK4a/p21waf1/hTERT) marker detection. The impact of DPSC expansion on mesenchymal, embryonic, and neural crest marker expression was assessed, as were the susceptibilities of high and low proliferative DPSCs to oxidative DNA and protein damage by immunocytochemistry. Expression profiles for superoxide dismutases (SODs), catalase, and glutathione-related antioxidants were further compared between DPSC sub-populations by qRT-PCR, Western blotting and activity assays. Results High proliferative DPSCs underwent > 80PDs in culture and resisted H2O2−induced senescence (50–76PDs). In contrast, low proliferative sub-populations exhibited accelerated senescence (4–32PDs), even in untreated controls (11-34PDs). While telomere lengths were largely unaffected, certain stem cell marker expression declined with H2O2 treatment and expansion. Elevated senescence susceptibilities in low proliferative DPSC (2–10PDs) were accompanied by increased oxidative damage, absent in high proliferative DPSCs until 45–60PDs. Increased SOD2/glutathione S-transferase ζ1 (GSTZ1) expression and SOD activities were identified in high proliferative DPSCs (10–25PDs), which declined during expansion. Low proliferative DPSCs (2–10PDs) exhibited inferior SOD, catalase and glutathione-related antioxidant expression/activities. Conclusions Significant variations exist in the susceptibilities of DPSC sub-populations to oxidative damage and premature senescence, contributed to by differential SOD2 and GSTZ1 profiles which maintain senescence-resistance/stemness properties in high proliferative DPSCs. Identification of superior antioxidant properties in high proliferative DPSCs enhances our understanding of DPSC biology and senescence, which may be exploited for selective sub-population screening/isolation from dental pulp tissues for regenerative medicine-based applications.

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Age-Related Changes in Expression and Activity of Human Hepatic Mitochondrial Glutathione Transferase Zeta1

Cited by 9 publications

References 55 publications

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes

Differential SOD2 and GSTZ1 profiles contribute to contrasting dental pulp stem cell susceptibilities to oxidative damage and premature senescence

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