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Article

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

1
Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland
2
Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland
3
Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, 4055 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(7), 212; https://doi.org/10.3390/biomedicines8070212
Received: 17 June 2020 / Revised: 8 July 2020 / Accepted: 10 July 2020 / Published: 14 July 2020
(This article belongs to the Section Tumor Cell Biology)
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. View Full-Text
Keywords: metamizole; agranulocytosis; mechanism; glycolysis; mitochondria metamizole; agranulocytosis; mechanism; glycolysis; mitochondria
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MDPI and ACS Style

Rudin, D.; Schmutz, M.; Roos, N.J.; Bouitbir, J.; Krähenbühl, S. Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis. Biomedicines 2020, 8, 212. https://doi.org/10.3390/biomedicines8070212

AMA Style

Rudin D, Schmutz M, Roos NJ, Bouitbir J, Krähenbühl S. Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis. Biomedicines. 2020; 8(7):212. https://doi.org/10.3390/biomedicines8070212

Chicago/Turabian Style

Rudin, Deborah, Maurice Schmutz, Noëmi J. Roos, Jamal Bouitbir, and Stephan Krähenbühl. 2020. "Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis" Biomedicines 8, no. 7: 212. https://doi.org/10.3390/biomedicines8070212

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