Cytochrome P450-dependent toxicity of dapsone in human erythrocytes
The most prominent adverse effects seen during treatment with dapsone, an antibacterial and antiprotozoal agent, are hemolysis and methemoglobinemia. An in vitro microsomal/cytochrome P450 (CYP)‐linked assay, which allows reactive metabolites generated in situ to react with the co‐incubated human er...
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Veröffentlicht in: | Journal of applied toxicology 2010-04, Vol.30 (3), p.271-275 |
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Sprache: | eng |
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Zusammenfassung: | The most prominent adverse effects seen during treatment with dapsone, an antibacterial and antiprotozoal agent, are hemolysis and methemoglobinemia. An in vitro microsomal/cytochrome P450 (CYP)‐linked assay, which allows reactive metabolites generated in situ to react with the co‐incubated human erythrocytes, was employed to profile CYP isoforms responsible for hemotoxicity of dapsone. Dapsone caused a robust generation of methemoglobin in human erythrocytes in the presence of human/mouse liver microsomes, which indicates contribution of CYP‐mediated metabolism for hemotoxicity. The highest methemoglobin formation with dapsone was observed with CYP2C19, with minor contributions from CYP2B6, CYP2D6 and CYP3A4. Cimetidine and chloramphenicol completely abrogated methemoglobin generation by dapsone, thus confirming a predominant contribution of CYP2C19. The results provide useful insights into CYP‐dependent hemotoxicity of dapsone in human erythrocytes. Copyright © 2009 John Wiley & Sons, Ltd.
Dapsone metabolites generated through cytochrome P450 (CYP) mediated reactions are responsible for its hemolytic side effects. An in vitro metabolism‐linked assay was employed to profile CYP isoforms responsible for hemotoxicity of dapsone. The metabolism through CYP 2C19 contributed maximally to its hemotoxic effects with minor contributions from CYP2B6, CYP2D6 and CYP3A4. Abrogation of hemotoxic effects of dapsone by cimetidine and chloramphenicol further confirmed predominant contribution of CYP2C19 mediated metabolism. |
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ISSN: | 0260-437X 1099-1263 1099-1263 |
DOI: | 10.1002/jat.1493 |