Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle

Boquist, Lennart; Ericsson, I.

doi:10.1016/0014-5793(84)80609-2

Cited by 18 publications

(9 citation statements)

References 18 publications

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“…In these studies, damage to intracellular constituents was found to precede functional injuries which result in the release of 51Cr from pre-labelled ceils. Furthermore, our results correspond to previous findings describing mitochondrial dysfunction as an early event in the process of Beta-cell damage after exposure to the diabetogenic drugs alloxan [35] and streptozotocin [36] or to the cytokines tumour necrosis factor [37] and interleukin-1 [38]. The sequence of injuries may be explained by the different effectiveness of repair systems in the two cellular components.…”

Section: Burkart Et Al: Oxygen Radicals Lyse Pancreatic Islet Cellssupporting

confidence: 90%

Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro

et al. 1992

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Summary. The endothelium-associated enzyme xanthine oxidase is known to generate reactive oxygen intermediates which may damage the surrounding tissue. We investigated whether reactive oxygen intermediates released by xanthine oxidase exert a toxic effect on isolated rat islet cells. The xanthine oxidase (25 mU/ml)/hypoxanthine (0.5 mmol/1) system released reactive oxygen intermediates in vitro as detected by luminol in a chemiluminescence analysing system. The addition of nicotinamide inhibited the release of reactive oxygen intermediates in a dose-dependent manner (50 % inhibition at 20 retool/l). Exposure of islet cells to enzyme generated reactive oxygen intermediates caused lysis of 39 % of the cells within 15 h. Monitoring the mitochondrial function of islet cells by the conversion of tetrazolium bromide to its formazan product revealed a significant reduction of the respiratory activity down to 51% of that of the controls by 30 min after the initiation of the xanthine oxidase reaction. Mitochondrial dysfunction preceded plasma membrane damage. The addition of nicotinamide, a radical scavenger and inhibitor of the DNA repair enzyme poly(ADP-ribose) synthetase protected the islet cells from lysis and partially preserved their mitochondrial activity in the presence of reactive oxygen intermediates. We conclude that activation of the endothelial enzyme xanthine oxidase, known to be induced by mediators of immune cells or by episodes of ischaemia and reperfusion causes islet cell damage with subsequent cell death in early phases of pancreatic islet cell destruction.

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Section: Burkart Et Al: Oxygen Radicals Lyse Pancreatic Islet Cellssupporting

confidence: 90%

Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro

et al. 1992

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“…The mitochondrial aconitase activity was determined as previously described (without activation) [6]. The oxygen consumption of isolated mitochondria was determined at 2YC with a Clark-type electrode and 1 mg mitochondriaf protein/ml, in a medium containing 200 mM sucrose, 10 mM Hepes, The concentration of citrate was determined enzymatically, using instant freezing in situ for liver and kidneys, and (for technical reasons) using freeze-dried specimens of islets according to [lo].…”

Section: Methodsmentioning

confidence: 99%

Alterations in mitochondrial aconitase activity and respiration, and in concentration of citrate in some organs of mice with experimental or genetic diabetes

et al. 1985

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Mouse islets {not used for respiration), kidneys and liver were studied in early and manifest alloxan diabetes, and in genetic diabetes. In these organs the mito~hondrial aconitase activity was lower, state 3 respiration with citrate or pyruvate plus malate (but not with succinate) was decreased, and the concentration of citrate was increased, compared with non-diabetic control mice. The alterations suggest a role of lowered activity of mitochondrial aconitase in alloxan diabetes, and probably also in genetic diabetes. Aconitase

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“…Alloxan, a known inhibitor of mitochondrial aconitase and other enzymes associated with the citric acid cycle [ 46 ], was tested at the same concentration in two studies [ 5 , 6 ]. However, in the O'Brien et al [ 5 ], study, alloxan showed changes only in the mitochondrial potential, suggesting that HepG2 cells may be more sensitive than primary human hepatocytes.…”

Section: Comparison Of Compounds Studiedmentioning

confidence: 99%

High-Content Screening: Understanding and Managing Mechanistic Data to Better Predict Toxicity

Walker

Smith

Frost

et al. 2015

Methods in Pharmacology and Toxicology

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An increased understanding of the cellular pathways involved in toxicity responses, coupled with a simultaneous advance in technology, has allowed for a shift in the way that the safety assessment of novel chemicals is performed. The development of assays that offer a high-throughput and low-cost option in comparison to more traditional approaches has been a focus of recent years.Early identifi cation of compounds which have the potential to cause Drug Induced Liver Injury (DILI) remains a major challenge for the pharmaceutical industry. Improvements in the mechanistic understanding of the cellular processes involved in this complex response have allowed for models to be generated and more reliable predictions to be made.High-Content Screening (HCS) describes an approach whereby multiple end points can be monitored in a single assay. The focus of this chapter is to introduce HCS with relation to using automated fl uorescence microscopy in order to assess phenotypic changes within cells and, more specifi cally, how this can be incorporated into the drug discovery process.We discuss the advantages that HCS can offer, whilst highlighting important factors to take into account when considering establishing the approach within a laboratory. Four papers whereby HCS has been used to highlight the potential of compounds to cause DILI are reviewed and compared. In addition, an option for including HCS as part of a wider workfl ow to identify environmental toxicants is introduced.

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Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle

Cited by 18 publications

References 18 publications

Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro

Oxygen radicals generated by the enzyme xanthine oxidase lyse rat pancreatic islet cells in vitro

Alterations in mitochondrial aconitase activity and respiration, and in concentration of citrate in some organs of mice with experimental or genetic diabetes

High-Content Screening: Understanding and Managing Mechanistic Data to Better Predict Toxicity

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