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

Deborah Rudin,Noëmi Johanna Roos,Stephan Krähenbühl,Jamal Bouitbir,Maurice Schmutz

doi:10.3390/biomedicines8070212

Deborah Rudin, Noëmi Johanna Roos + Show 3 more

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https://doi.org/10.3390/biomedicines8070212

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Journal: Biomedicines	Publication Date: Jul 14, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: University Hospital of Basel, University of Basel

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.

Highlights

IntroductionMetamizole (dipyrone) is an analgesic and antipyretic drug that is used frequently in human and veterinary practice in some countries in Europe and South America but has been withdrawn from the market in other countries such as for instance Sweden, England, and the United States
Metamizole is an analgesic and antipyretic drug that is used frequently in human and veterinary practice in some countries in Europe and South America but has been withdrawn from the market in other countries such as for instance Sweden, England, and the United States
The current study shows that MAA enhanced the toxic effect of hemin on glycolysis but not on mitochondrial function andthat that alone did impair metabolism of HL60 cells

Summary

Introduction

Metamizole (dipyrone) is an analgesic and antipyretic drug that is used frequently in human and veterinary practice in some countries in Europe and South America but has been withdrawn from the market in other countries such as for instance Sweden, England, and the United States. MAA has a bioavailability close to 100% and is the main metabolite circulating in plasma [4,5].The analgesic activity of metamizole. It can cause anaphylaxis [7,8] and skin eruptions, which are considered to result from delayed allergic reactions [9,10]. The most severe adverse reaction is myelotoxicity, mostly in the form of neutropenia or agranulocytosis [11]. The frequency of this reaction is not exactly known and depends on the method used for its determination; estimates range from 1:1500 of patients treated [12] to approximately 1 per million person days of use [13] and

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