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Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis

Rudin, Deborah and Schmutz, Maurice and Roos, Noëmi Johanna and Bouitbir, Jamal and Krähenbühl, Stephan. (2020) Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis. Biomedicines, 8 (7). p. 212.

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Official URL: https://edoc.unibas.ch/78276/

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Abstract

Metamizole is an analgesic, whose pharmacological and toxicological properties are attributed to N-methyl-aminoantipyrine (MAA), its major metabolite. In the presence of heme iron, MAA forms reactive metabolites, which are toxic for granulocyte precursors. Since decreased cellular ATP is characteristic for MAA-associated toxicity, we studied the effect of MAA with and without hemin on energy metabolism of HL60 cells, a granulocyte precursor cell line. The combination MAA/hemin depleted the cellular ATP stronger than hemin alone, whereas MAA alone was not toxic. This decrease in cellular ATP was observed before plasma membrane integrity impairment. MAA/hemin and hemin did not affect the proton leak but increased the maximal oxygen consumption by HL60 cells. This effect was reversed by addition of the radical scavenger; N; -acetylcysteine. The mitochondrial copy number was not affected by MAA/hemin or hemin. Hemin increased mitochondrial superoxide generation, which was not accentuated by MAA. MAA decreased cellular ROS accumulation in the presence of hemin. In cells cultured in galactose (favoring mitochondrial ATP generation), MAA/hemin had less effect on the cellular ATP and plasma membrane integrity than in glucose. MAA/hemin impaired glycolysis more than hemin or MAA alone, and; N; -acetylcysteine blunted this effect of MAA/hemin. MAA/hemin decreased protein expression of pyruvate kinase more than hemin or MAA alone. In conclusion, cellular ATP depletion appears to be an important mechanism of MAA/hemin toxicity on HL60 cells. MAA itself is not toxic on HL60 cells up to 100 µM but boosts the inhibitory effect of hemin on glycolysis through the formation of reactive metabolites.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
UniBasel Contributors:Bouitbir, Jamal and Roos, Noëmi Johanna and Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:MDPI AG
e-ISSN:2227-9059
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:29 Dec 2020 11:22
Deposited On:29 Dec 2020 11:22

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