Effect of metamizol on promyelocytic and terminally differentiated granulocytic cells. Comparative analysis with acetylsalicylic acid and diclofenac

Metamizol is an analgesic and antipyretic agent that can induce agranulocytosis in certain patients. However, its effects on granulocyte viability and differentiation have been poorly evaluated. Here we analysed the effects of metamizol and its active metabolite, 4-methylaminoantipyrine (MAA), on the viability of HL60 promyelocytes and their dimethyl sulphoxide-induced differentiated granulocytes. Metamizol and MAA at 75 microM (above the peak of plasmatic concentration after 2g intake) did not alter granulocytic differentiation of HL60 cells. Only at concentrations above 100 microM, well over the pharmacological range, metamizol-induced apoptosis in about 30% of the HL60 promyelocytes, while HL60-granulocytic terminally differentiated cells were more resistant to this apoptotic action. When the effects of metamizol were compared with those of acetylsalicylic acid (ASA) and diclofenac on cell viability, at equivalent concentrations used in analgesic and antipyretic therapy (75 microM for metamizol, and ASA and 3 microM for diclofenac) their apoptotic effects were similar. Again, the HL60 promyelocytes were more sensitive to apoptosis than granulocytic differentiated cells, as measured by the percentage of sub-G(1) cells detected by flow cytometry and by determination of caspase activity as a function of poly(ADP-ribose) polymerase cleavage. Furthermore, when human blood-derived granulocytes were treated with metamizol, MAA, and ASA at 75 microM or diclofenac at 3 microM, less than 10% of apoptotic granulocytes were detected, whereas at toxicological/suprapharmacological concentrations (10mM), about 90% of granulocytes were apoptotic. These results demonstrate that metamizol, MAA, ASA, and diclofenac, at pharmacological concentrations, neither affect the granulocytic differentiation process nor induce relevant apoptosis on terminally differentiated granulocytes.