title: Activation of CYP2C9-mediated metabolism by a series of dapsone analogs: kinetics and structural requirements.
abstract: Cytochrome P450 2C9-mediated metabolism has been shown to be activated in the presence of the effector dapsone. However, it has yet to be established what effector structural features are necessary to activate CYP2C9 activity. To address this question, kinetic studies were conducted with nine analogs of dapsone containing various functional properties (three sulfone compounds, three carbonyl compounds, and three sulfonamide compounds), to examine the functional groups important for enzyme activation by the effector (dapsone). Results show that phenylsulfone (dapsone without the para-amino groups) activates flurbiprofen 4'-hydroxylation comparable to dapsone but inhibits naproxen demethylation. Meanwhile, p-tolylsulfone had little effect on flurbiprofen metabolism, but activated naproxen demethylation, albeit only at high concentrations. These substrate-dependent differences in effect suggest that naproxen has a different binding orientation compared with flurbiprofen. Perhaps most interesting is that replacement of only one amino group from dapsone with a nitro group (4-(4-nitrophenylsulfonyl)-aniline) resulted in substantial inhibition of flurbiprofen 4'-hydroxylation, suggesting that electronic effects may influence activation of this substrate. Other analogs either had minor or no effect on CYP2C9-mediated metabolism. Overall, it is apparent from these studies that a sulfone group in direct association with two benzene rings with para-electron-donating groups represents the most efficient activator of CYP2C9. However, the effects of these analogs appear to be concentration- and substrate-dependent, further complicating the prediction of these types of in vitro interactions.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Hutzler
authors.forename: Dhanashri
authors.initials: D
authors.lastname: Kolwankar
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hummel
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Tracy
mesh_terms: D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D003622:Dapsone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D003640:Dealkylation; D005480:Flurbiprofen / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D009288:Naproxen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen; D005480:Flurbiprofen; D003622:Dapsone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases