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 P(450) (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.
Ganesan
Shobana
S
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Sahu
Rajnish
R
Walker
Larry A
LA
Tekwani
Babu L
BL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000633:toxicity; D000981:Antiprotozoal Agents / Q000378:metabolism / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001711:Biotransformation; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000378:metabolism* / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects*; D053878:Hemolytic Agents / Q000378:metabolism* / Q000633:toxicity*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009994:Osmolar Concentration; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D053878:Hemolytic Agents; D007527:Isoenzymes; D011994:Recombinant Proteins; D003622:Dapsone; D008706:Methemoglobin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating