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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.
Drug Metab Dispos. 1994 Jul-Aug; 22(4):572-7.DM

Abstract

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.

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Authors+Show Affiliations

Vage C
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202.
Svensson CK
No affiliation info available

MeSH

AcetylcysteineAnimalsAnti-Infective AgentsAntibodies, MonoclonalAryl Hydrocarbon HydroxylasesBiotransformationCimetidineCytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemCytochrome P450 Family 2DapsoneDexamethasoneFemaleMaleMembrane ProteinsMicrosomes, LiverRatsRats, Sprague-DawleySex FactorsSteroid 16-alpha-HydroxylaseSteroid HydroxylasesTroleandomycin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7956732

Citation

Vage, C, and C K. Svensson. "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." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 22, no. 4, 1994, pp. 572-7.
Vage C, Svensson CK. 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. Drug Metab Dispos. 1994;22(4):572-7.
Vage, C., & Svensson, C. K. (1994). 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. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 22(4), 572-7.
Vage C, Svensson CK. 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. Drug Metab Dispos. 1994 Jul-Aug;22(4):572-7. PubMed PMID: 7956732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Vage,C, AU - Svensson,C K, PY - 1994/7/1/pubmed PY - 1994/7/1/medline PY - 1994/7/1/entrez SP - 572 EP - 7 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 22 IS - 4 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/7956732/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_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7956732 DB - PRIME DP - Unbound Medicine ER -