Evidence that the biotransformation of dapsone and monoacetyldapsone to their respective hydroxylamine metabolites in rat liver microsomes is mediated by cytochrome P450 2C6/2C11 and 3A1.

The formation of dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine (MADDS-NOH) was found to be greater in male vs. female rat liver microsomes, suggesting a role for either CYP2C11 or CYP3A2. Preincubation with cimetidine (selective for inhibition of CYP2C11), but not troleandomycin (selective for inhibition of CYP3A1/2), inhibited metabolite formation. Furthermore, incubation with monoclonal antibodies (Mabs) to CYP2C6/2C11 reduced metabolite formation to below the level of detection. Together, these data indicate that N-hydroxylation of DDS and MADDS in rat liver microsomes from untreated male rats is catalyzed by CYP2C6/2C11. Interestingly, dexamethasone pretreatment increased the hydroxylation of both metabolites. Preincubation with cimetidine or Mabs to CYP2C6/2C11 (at an antibody:protein ratio of 26:1) in microsomes from dexamethasone pretreated animals did not reduce the N-hydroxylation of DDS, whereas preincubation with troleandomycin reduced metabolite formation by > or = 50%. Collectively, these data indicate that the constitutive enzymes CYP2C6 and/or CYP2C11, as well as CYP3A1 (nonconstitutive), are capable of catalyzing the hydroxylation of DDS and MADDS.