JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 20, 2006; DOI: 10.1124/jpet.106.105874

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.106.105874v1
319/1/497    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vyas, P. M
Right arrow Articles by Svensson, C. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vyas, P. M
Right arrow Articles by Svensson, C. K.


Received for publication April 7, 2006.
Revised June 14, 2006.
Accepted for publication July 19, 2006.

Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes - 2. Expression and role of flavin-containing monooxygeanses and peroxidases

Piyush M Vyas 1, Sanjoy Roychowdhury 1, Sevasti B. Koukouritaki 2, Ronald N. Hines 2, Sharon K. Krueger 3, David E. Williams 3, William M. Nauseef 1, Craig K. Svensson 1*

1 The University of Iowa 2 Medical College of Wisconsin 3 Oregon State University

* Address correspondence to: E-mail: craig-svensson{at}uiowa.edu

Abstract

Arylamine compounds, such as sulfamethoxazole (SMX) and dapsone (DDS), are metabolized in epidermal keratinocytes to arylhydroxylamine metabolites that auto-oxidize to arylnitroso derivatives, which in turn bind to cellular proteins and can act as antigens/immunogens. Previous studies have demonstrated that neither cytochromes P450 nor cyclooxygenases mediate this bioactivation in normal human epidermal keratinocytes (NHEK). In this investigation, we demonstrated that methimazole (MMZ), a prototypical substrate of the flavin-containing monooxygenases (FMOs), attenuated the protein haptenation observed in NHEK exposed to SMX or DDS. In addition, recombinant FMO1 and FMO3 were able to bioactivate both SMX and DDS, resulting in covalent adduct formation. Western blot analysis confirmed the presence of FMO3 in NHEK, whereas FMO1 was not detectable. In addition to MMZ, 4-aminobenzoic acid hydrazide (ABH) also attenuated SMX- and DDS-dependent protein haptenation in NHEK. ABH did not alter the bioactivation of these drugs by recombinant FMO3, suggesting its inhibitory effect in NHEK was due to its known ability to inhibit peroxidases. Studies confirmed the presence of peroxidase activity in NHEK, however, immunoblot analysis and RT-PCR indicated that myeloperoxidase, lactoperoxidase and thyroid peroxidase were absent. Thus, our results suggest an important role for FMO3 and yet to be identified peroxidases in the bioactivation of sulfonamides in NHEK.


Key words: dapsone, flavin monooxygenase, keratinocytes, peroxidases, protein haptenation, sulfamethoxazole


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
S. Roychowdhury, P. M. Vyas, and C. K. Svensson
Formation and Uptake of Arylhydroxylamine-Haptenated Proteins in Human Dendritic Cells
Drug Metab. Dispos., April 1, 2007; 35(4): 676 - 681.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.