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CYP 2C19 IS PRIMARILY RESPONSIBLE FOR METHEMOGLOBIN TOXICITY OF DAPSONE
Author(s) -
Ganesan Shobana,
Tekwani Babu,
Walker Larry
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a196-c
Subject(s) - methemoglobin , dapsone , methemoglobinemia , toxicity , microsome , pharmacology , chemistry , oxidative stress , biochemistry , biology , hemoglobin , in vitro , immunology , organic chemistry
Dapsone (4,4′‐ Diaminodiphenylsulphone; DDS) is a potent antibacterial and antiprotozoal agent and also used in treatment of leprosy and inflammation. Adverse effects with DDS are hemolysis and methemoglobinemia, particularly in patients with glucose‐6‐phosphate dehydrogenase deficiency. An in vitro assay which allows stable & unstable metabolites generated in situ to react with the human erythrocytes, has been employed to study CYP mediated hemotoxicity toxicity of DDS. Pooled human/mouse liver microsomes and supersomes with recombinant human CYPs were used to profile CYPs responsible for methemoglobinemia and oxidative stress. Metabolism of DDS by 2C19 caused highest methemoglobin toxicity with minor contributions of 2B6, 2D6 and 3A4. CYP 2C8 and 2C9, which have been shown to metabolize DDS to DDS‐NOH, the toxic metabolite, did not show significant role in methemoglobin toxicity of DDS. Cimetidine and chloramphemicol completely abolished the methemoglobin toxicity of DDS in human liver microsomes and recombinant human 2C19. DDS‐NOH generated dose dependent methemoglobin toxicity, oxidative stress and also caused Heinz body formation in human erythrocytes. Dapsone however did not generate significant oxidative stress in presence of human liver microsomes or recombinant human CYPs. These studies indicate predominant role of 2C19 in methemoglobin toxicity of dapsone. Supported by MMV, Geneva.