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Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes.
Journal article

Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes.

  • Rudin D Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. Electronic address: deborah.rudin@unibas.ch.
  • Roos NJ Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. Electronic address: noemi.roos@unibas.ch.
  • Duthaler U Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. Electronic address: urs.duthaler@unibas.ch.
  • Krähenbühl S Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031, Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), Missionsstrasse 64, 4055, Basel, Switzerland. Electronic address: stephan.kraehenbuehl@usb.ch.
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  • 2019-07-30
Published in:
  • Toxicology. - 2019
Antioxidative defense system
Glutathione
HL60 cell differentiation
Heme metabolism
Metamizole
N-methyl-4-aminoantipyrine (MAA)
Anti-Inflammatory Agents, Non-Steroidal
Antioxidants
Antipyrine
Apoptosis
Cell Differentiation
Cell Proliferation
Cell Survival
Dipyrone
Fetal Blood
Granulocytes
HL-60 Cells
Heme Oxygenase-1
Hemin
Humans
Neutrophils
Tumor Stem Cell Assay
English Metamizole is an analgesic and antipyretic with a superior analgesic efficacy than paracetamol. Since metamizole can cause neutropenia and agranulocytosis, it is currently used in only few countries. In a previous study, we have shown that N-methyl-4-aminoantipyrine (MAA), the active metamizole metabolite, reacts with hemin and forms an electrophilic metabolite that is toxic for HL60 cells, but not for mature neutrophil granulocytes. In the current study, we investigated the toxicity of hemin (12.5 μM) and MAA (100 μM) on differentiating HL60 cells. In undifferentiated HL60 cells, hemin decreased the viability and this effect was significantly increased by MAA. Similarly, hemin/MAA was more toxic than hemin alone on human cord blood cells. At 3 days (metamyelocyte stage) and 5 days of differentiation (mature neutrophils), hemin/MAA was not toxic on HL60 cells, whereas hemin alone was still toxic. No toxicity was observed on freshly isolated human neutrophils. The protein expression of enzymes responsible for hemin metabolism increased with HL60 cell differentiation. Inhibition of heme oxygenase-1 or cytochrome P450 reductase increased the toxicity of hemin and hemin/MAA in undifferentiated, but only for hemin in differentiated HL60 cells. Similar to the enzymes involved in hemin metabolism, the protein expression of enzymes involved in antioxidative defense and the cellular glutathione pool increased with HL60 cell differentiation. In conclusion, HL60 cells become resistant to the toxicity of hemin/MAA and partly also of hemin during their differentiation. This resistance is associated with the development of heme metabolism and of the antioxidative defense system including the cellular glutathione pool.
Language
  • English
Open access status
closed
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Persistent URL
https://sonar.rero.ch/global/documents/73378
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