Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 byN-(α-Methylbenzyl)-1-Aminobenzotriazole

Christopher J. Sinal, Maurice Hirst, Christopher D. Webb and John R. Bend
Drug Metabolism and Disposition July 1998, 26 (7) 681-688;
Christopher J. Sinal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maurice Hirst
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher D. Webb
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John R. Bend
  • 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

N-Aralkylated derivatives of 1-aminobenzotriazole are well-established, mechanism-based inhibitors of cytochrome P450 (CYP or P450). In this study, the kinetics of inactivation of CYP2B-dependent 7-pentoxyresorufin O-depentylation (PROD) and CYP1A-dependent 7-ethoxyresorufin O-deethylation (EROD) activities by enantiomers ofN-(α-methylbenzyl)-1-aminobenzotriazole (αMB) were compared. The racemic mixture (±)-αMB, as well as the enantiomers (−)-αMB and (+)-αMB, produced a time-, concentration-, and NADPH-dependent loss of PROD and EROD activity in hepatic microsomes from phenobarbital-treated guinea pigs. The rates of PROD inactivation by (−)-αMB were significantly faster than for (+)-αMB. Consistent with this, the derived maximal kinact was also significantly greater for (−)-αMB than for (+)-αMB (0.49vs. 0.35 min−1). In contrast, the concentrations required for the half-maximal rate of inactivation (Ki ) were equivalent for (−)-αMB and (+)-αMB, whereas the degree of competitive inhibition of PROD activity was greater for (+)-αMB. No significant differences were found among (−)-αMB, (+)-αMB, and (±)-αMB with respect to mechanism-based inactivation (kinact = 0.18, 0.16, and 0.17 min−1, respectively) or competitive inhibition of EROD activity. No differences were found for the maximal extent of PROD or EROD inhibition or the loss of spectral P450 after an extended 30-min incubation with the inhibitors. We conclude that mechanism-based inactivation of guinea pig CYP2B, but not CYP1A, isozymes by αMB occurs in a stereoselective manner, most likely as a result of a difference in the balance between metabolic activation and deactivation for the αMB enantiomers.

Footnotes

  • Send reprint requests to: Dr. John R. Bend, Department of Pharmacology and Toxicology, Medical Sciences Building, Room 275, University of Western Ontario, London, Ontario, Canada N6A 5C1.

  • This work was supported by the Medical Research Council of Canada (Grant MT9972 to J.R.B.) and by the Academic Development Fund, University of Western Ontario. C.J.S. is the recipient of an Ontario Graduate Scholarship.

  • Abbreviations used are::
    P450 or CYP
    cytochrome P450
    ABT
    1-aminobenzotriazole
    BBT
    N-benzyl-1-aminobenzotriazole
    αMB
    N-(α-methylbenzyl)-1-aminobenzotriazole
    PROD
    7-pentoxyresorufin O-depentylation
    EROD
    7-ethoxyresorufin O-deethylation
    • Received November 26, 1997.
    • Accepted March 20, 1998.
  • 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
Vol. 26, Issue 7
1 Jul 1998
  • Table of Contents
  • Index by author
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.
Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 byN-(α-Methylbenzyl)-1-Aminobenzotriazole
(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

Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 byN-(α-Methylbenzyl)-1-Aminobenzotriazole

Christopher J. Sinal, Maurice Hirst, Christopher D. Webb and John R. Bend
Drug Metabolism and Disposition July 1, 1998, 26 (7) 681-688;

Citation Manager Formats

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

Share
Research ArticleArticle

Enantioselective, Mechanism-Based Inactivation of Guinea Pig Hepatic Cytochrome P450 byN-(α-Methylbenzyl)-1-Aminobenzotriazole

Christopher J. Sinal, Maurice Hirst, Christopher D. Webb and John R. Bend
Drug Metabolism and Disposition July 1, 1998, 26 (7) 681-688;
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • TMDD Affects PK of IL-10 Fc-Fusion Proteins
  • In Vitro Models to Study P-gp-Mediated Intestinal DDIs
  • Covalent Inactivation of CYP3A by Futibatinib
Show more Article

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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics