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), b ut not troleandomycin (selective for inhibition of CYP3A1/2), inhibite d metabolite formation. Furthermore, incubation with monoclonal antibo dies (Mabs) to CYP2C6/2C11 reduced metabolite formation to below the l evel of detection. Together, these data indicate that N-hydroxylation of DDS and MADDS in rat liver microsomes from untreated male rats is c atalyzed by CYP2C6/2C11. Interestingly, dexamethasone pretreatment inc reased the hydroxylation of both metabolites. Preincubation with cimet idine 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 reduc ed metabolite formation by greater than or equal to 50%. Collectively, these data indicate that the constitutive enzymes CYP2C6 and/or CYP2C 11, as well as CYP3A1 (nonconstitutive), are capable of catalyzing the hydroxylation of DDS and MADDS.