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

1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor of N-Acetyltransferase

Q. Sun, T. W. Harper, E. A. Dierks, L. Zhang, S. Chang, A. D. Rodrigues and P. Marathe
Drug Metabolism and Disposition September 2011, 39 (9) 1674-1679; DOI: https://doi.org/10.1124/dmd.111.039834
Q. Sun
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
T. W. Harper
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E. A. Dierks
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Chang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. D. Rodrigues
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. Marathe
  • 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

1-Aminobenzotriazole (ABT) has been used widely as a nonselective in vitro and in vivo inhibitor of cytochrome P450 enzymes. To date, however, it has not been evaluated as an inhibitor of UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT). In the present study, ABT was shown not to inhibit UGT and SULT activity (acetaminophen and 7-hydroxycoumarin as substrates) in rat liver microsomes and rat liver 9000g supernatant fraction (RLS9), respectively. However, it did inhibit the RLS9-catalyzed N-acetylation of procainamide (IC50 ∼ 30 μM), and no preincubation time dependence was evident. In agreement, oral ABT (100 mg/kg, 2 h predose) decreased the clearance of intravenous procainamide (45%) in rats, accompanied by a decreased N-acetylprocainamide-to-procainamide ratio in urine (0.74 versus 0.21) and plasma (area under the curve ratio 0.59 versus 0.11). Additional studies with human forms of NAT (hNAT1 and hNAT2) revealed that ABT is a more potent inhibitor of hNAT2 compared with hNAT1 (IC50 158 μM versus > 1 mM). Consistent with the IC50 estimate, formal inhibition studies revealed that inhibition of hNAT2 was competitive with an inhibition constant of 67 μM. In accordance with the competitive inhibition, ABT was shown to undergo N-acetylation in the presence of both human NAT forms, with hNAT1 exhibiting less activity under the same assay conditions (∼40% of hNAT2). In summary, the results described herein indicate that ABT is a substrate and inhibitor of NAT. Such an interaction should be considered when using ABT as a nonselective inhibitor of P450, especially when NAT-dependent metabolism is also involved.

Footnotes

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

    doi:10.1124/dmd.111.039834.

  • ABBREVIATIONS:

    ABT
    1-aminobenzotriazole
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    SULT
    sulfotransferase
    NAT
    N-acetyltransferase
    RLS9
    rat liver 9000g supernatant fraction
    hNAT
    human NAT
    UDPGA
    uridine-diphosphoglucuronic acid
    RLM
    rat liver microsomes
    PAPS
    3′-phosphoadenosine 5′-phosphosulfate
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    AUC
    area under the curve
    CL
    clearance
    PK
    pharmacokinetics.

  • Received April 5, 2011.
  • Accepted June 15, 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 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 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.
1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor of N-Acetyltransferase
(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

1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor of N-Acetyltransferase

Q. Sun, T. W. Harper, E. A. Dierks, L. Zhang, S. Chang, A. D. Rodrigues and P. Marathe
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1674-1679; DOI: https://doi.org/10.1124/dmd.111.039834

Citation Manager Formats

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

1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor of N-Acetyltransferase

Q. Sun, T. W. Harper, E. A. Dierks, L. Zhang, S. Chang, A. D. Rodrigues and P. Marathe
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1674-1679; DOI: https://doi.org/10.1124/dmd.111.039834
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

  • Retroconversion of PQ and Its N-Oxide Metabolites
  • Deoxycholate Oxidation Is Predictive of CYP3A Activity
  • REF vs RAF Prediction of Renal Clearance
Show more Articles

Similar Articles

Advertisement
  • 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