Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

Agnieszka Potega, Emilia Dabrowska, Magdalena Niemira, Agata Kot-Wasik, Sebastien Ronseaux, Colin J. Henderson, C. Roland Wolf and Zofia Mazerska
Drug Metabolism and Disposition August 2011, 39 (8) 1423-1432; DOI: https://doi.org/10.1124/dmd.111.038984
Agnieszka Potega
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emilia Dabrowska
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Magdalena Niemira
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Agata Kot-Wasik
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sebastien Ronseaux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colin J. Henderson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Roland Wolf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zofia Mazerska
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8-methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDP-glucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, PFMO, which is identified as an N-oxide derivative, was identical to P3R of liver microsomes. P3R was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3R = PFMO. Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C-1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1.

Footnotes

  • This work was supported in part by the Ministry of Science and Higher Education (Poland) [Grant N401 159 32/3045]; the British-Polish Young Scientists Programme [WAR/342/84] of British Council; and Cancer Research UK [C4639/A5661] (to C.R.W.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.038984.

  • ABBREVIATIONS:

    C-1311
    5-diethylaminoethylamino-8-hydroxyimidazoacridinone
    C-1330
    5-diethylaminoethylamino-8-methoxyimidazoacridinone
    HPLC
    high-performance liquid chromatography
    RPK
    reaction phenotyping kit
    FMO
    flavin monooxygenase
    UGT
    UDP-glucuronosyltransferase
    P450
    cytochrome P450
    POR
    NADPH-P450 oxidoreductase
    1-ABT
    1-aminobenzotriazol
    GUS
    β-glucuronidase
    UDPGA
    UDP-glucuronic acid
    HLM
    human liver microsomes
    RLM
    rat liver microsomes
    MRA
    multiple regression analysis
    HRN
    hepatic reductase-null mouse
    ESI
    electrospray ionization
    MS
    mass spectrometry
    RP
    reverse-phase
    Vis
    visible
    WT
    wild-type
    PH-302
    2-((2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl) (3-((benzo-[d][1,3]dioxol-5-ylmethyl)(methyl)amino)propyl)amino)acetamide.

  • Received February 18, 2011.
  • Accepted May 9, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 39 (8)
Drug Metabolism and Disposition
Vol. 39, Issue 8
1 Aug 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

Agnieszka Potega, Emilia Dabrowska, Magdalena Niemira, Agata Kot-Wasik, Sebastien Ronseaux, Colin J. Henderson, C. Roland Wolf and Zofia Mazerska
Drug Metabolism and Disposition August 1, 2011, 39 (8) 1423-1432; DOI: https://doi.org/10.1124/dmd.111.038984

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

Agnieszka Potega, Emilia Dabrowska, Magdalena Niemira, Agata Kot-Wasik, Sebastien Ronseaux, Colin J. Henderson, C. Roland Wolf and Zofia Mazerska
Drug Metabolism and Disposition August 1, 2011, 39 (8) 1423-1432; DOI: https://doi.org/10.1124/dmd.111.038984
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • In Vivo Functional Effects of CYP2C9 M1L
  • Clearance pathways: fevipiprant with probenecid perpetrator
  • Predicting Volume of Distribution from In Vitro Parameters
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics