Cytochrome P₄₅₀‐dependent toxicity of dapsone in human erythrocytes

Abstract

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.

Prilocaine- and Lidocaine-Induced Methemoglobinemia Is Caused by Human Carboxylesterase-, CYP2E1-, and CYP3A4-Mediated Metabolic Activation

“…Methemoglobinemia is reported to be induced by certain types of clinically used drugs, including the analgesic antipyretic phenacetin, the antileprosy drug dapsone, and the antibiotic sulfamethoxazole (Reilly et al, 1999;Ganesan et al, 2010;Kobayashi et al, 2012), which all possess an aromatic amine moiety. N-Hydroxylamines, which are Nhydroxylated metabolites of aromatic amines, were suspected to be a cause of aromatic amine-induced methemoglobinemia (Spooren and Fig.…”

“…Thus, it is conceivable that CES1A, CES2, and AADAC are involved in the hydrolysis of prilocaine and lidocaine. Ganesan et al (2010) reported that dapsone-hydroxylamine, which is an N-hydroxylated metabolite of dapsone, was suspected to be a cause of dapsone-induced methemoglobinemia. The formation of dapsonehydroxylamine is catalyzed by cytochromes P450 (P450) CYP2C19, CYP2E1, and CYP3A4.…”

Clinical Oxidative Stress during Leprosy Multidrug Therapy: Impact of Dapsone Oxidation

“…Whilst the role of the hydroxylamine metabolites in dapsone toxicity is well established, the CYP isoforms primarily responsible for their formation have been the subject of considerable study in a variety of clinical and experimental models over past decades; indeed, CYP3A4, CYP2E1 and CYP2C9 [11]–[13] have each been postulated as the major contributor to the oxidation of this drug. Latterly, a role for CYP2C19, has been outlined in a study with recombinant isoforms [14] and in our report we also explore the potential interactions between dapsone and CYP2C19 using molecular docking analysis.…”

Rasburicase Causing Severe Oxidative Hemolysis and Methemoglobinemia in a Patient with Previously Unrecognized Glucose-6-Phosphate Dehydrogenase Deficiency

“…Despite encouraging in vitro evidence [24], N-acetylcysteine had no significant effect on nitrate-induced methemoglobinemia in two small human controlled trials [25,26]. The theoretical potential of cytochrome P450 (CYP450) inhibitors such as cimetidine is limited to methemoglobinemia induced by drugs such as dapsone and sulfasalazine, which are converted into their oxidant forms by CYP450 enzymes [27,28]. There are no reports of CYP450 inhibitor therapy in acute methemoglobinemia [29].…”