Dapsone‐Associated Methemoglobinemia in a Patient With Slow NAT2*5B Haplotype and Impaired Cytochrome b5 Reductase Activity

Dapsone (4,4′-diaminodiphenylsulfone; DDS) is a sulfone antimicrobial used to treat leprosy, malaria, and inflammatory dermatoses and to prevent and treat opportunistic infections in immunocompromised patients, particularly those who cannot tolerate sulfonamide antimicrobials.1 However, dapsone can lead to dose-dependent hematologic toxicity and is the most commonly recognized cause of acquired methemoglobinemia in human patients.2 The hydroxylamine metabolite of dapsone oxidizes the iron moiety of hemoglobin,3 which leads to increased levels of methemoglobin, impaired oxygen delivery, and cyanosis. Dapsone hydroxylamine is generated by CYP2C9 and CYP2C19, with minor contributions from other P450s.4,5 A rapid activity variant for CYP2C19 (CYP2C19*17) has been reported6 but not for CYP2C9. Dapsone hydroxylamine is detoxified by cytochrome b5 (b5) and its electron donor, cytochrome b5 reductase (b5R),7 which are expressed in blood, liver, and other tissues. This reduction pathway converts the hydroxylamine back to the parent dapsone. Dapsone itself is inactivated and eliminated following N-acetylation by the enzyme NAT2 in the liver,8 and impaired N-acetylation activity is a risk factor for hematologic and neurologic toxicity from dapsone.9,10 However, genotypic analysis of the CYP2C19, NAT2, and b5/b5R pathways has not been performed in the setting of dapsone-associated methemoglobinemia. This report describes a patient who developed methemoglobinemia at prophylactic dosages of dapsone, for which we characterized wild-type alleles at the CYP2C19*17 loci, but low activity of the b5/b5R pathway along with low expression of the CYB5A gene encoding b5, and a homozygous slow NAT2*5B haplotype, both of which may have contributed to defective dapsone detoxification.