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
Rapid CommunicationShort Communication

Respective Roles of CYP2A5 and CYP2F2 in the Bioactivation of 3-Methylindole in Mouse Olfactory Mucosa and Lung: Studies Using Cyp2a5-Null and Cyp2f2-Null Mouse Models

Xin Zhou, Jaime D'Agostino, Lei Li, Chad D. Moore, Garold S. Yost and Xinxin Ding
Drug Metabolism and Disposition April 2012, 40 (4) 642-647; DOI: https://doi.org/10.1124/dmd.111.044081
Xin Zhou
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jaime D'Agostino
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lei Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chad D. Moore
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Garold S. Yost
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xinxin Ding
  • 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 + SI
  • PDF
Loading

Abstract

The aim of this study was to determine whether mouse CYP2A5 and CYP2F2 play critical roles in the bioactivation of 3-methylindole (3MI), a tissue-selective toxicant, in the target tissues, the nasal olfactory mucosa (OM) and lung. Five metabolites of 3MI were identified in NADPH- and GSH-fortified microsomal reactions, including 3-glutathionyl-S-methylindole (GS-A1), 3-methyl-2-glutathionyl-S-indole (GS-A2), 3-hydroxy-3-methyleneindolenine (HMI), indole-3-carbinol (I-3-C), and 3-methyloxindole (MOI). The metabolite profiles and enzyme kinetics of the reactions were compared between OM and lung, and among wild-type, Cyp2a5-null, and Cyp2f2-null mice. In lung reactions, GS-A1, GS-A2, and HMI were detected as major products, and I-3-C and MOI, as minor metabolites. In OM reactions, all five metabolites were detected in ample amounts. The loss of CYP2F2 affected formation of all 3MI metabolites in the lung and formation of HMI, GS-A1, and GS-A2 in the OM. In contrast, loss of CYP2A5 did not affect formation of 3MI metabolites in the lung but caused substantial decreases in I-3-C and MOI formation in the OM. Thus, whereas CYP2F2 plays a critical role in the 3MI metabolism in the lung, both CYP2A5 and CYP2F2 play important roles in 3MI metabolism in the OM. Furthermore, the fate of the reactive metabolites produced by the two enzymes through common dehydrogenation and epoxidation pathways seemed to differ with CYP2A5 supporting direct conversion to stable metabolites and CYP2F2 supporting further formation of reactive iminium ions. These results provide the basis for understanding the respective roles of CYP2A5 and CYP2F2 in 3MI's toxicity in the respiratory tract.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Science [Grant ES007462]; the National Institutes of Health National Cancer Institute [Grant CA092596] (to X.D.); the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL13645]; and the National Institutes of Health National Institute of General Medical Sciences [Grant GM074249] (to G.S.Y.).

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

    http://dx.doi.org/10.1124/dmd.111.044081.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    3MI
    3-methylindole
    OM
    olfactory mucosa
    P450
    cytochrome P450
    MEI
    3-methyleneindolenine
    HMI
    3-hydroxy-3-methyleneindolenine
    MOI
    3-methyloxindole
    I-3-C
    indole-3-carbinol
    WT
    wild type
    GS-A1
    3-glutathionyl-S-methylindole (GSH adduct 1)
    APAP-GSH
    acetaminophen-GSH
    GS-A2
    3-methyl-2-glutathionyl-S-indole (GSH adduct 2)
    NNK-N-oxide
    4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-N-oxide
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    MIM
    multiple ion monitoring.

  • Received December 4, 2011.
  • Accepted December 22, 2011.
  • Copyright © 2012 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: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Respective Roles of CYP2A5 and CYP2F2 in the Bioactivation of 3-Methylindole in Mouse Olfactory Mucosa and Lung: Studies Using Cyp2a5-Null and Cyp2f2-Null Mouse Models
(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
Rapid CommunicationShort Communication

CYP2A5- AND CYP2F2-MEDIATED BIOACTIVATION OF 3-METHYLINDOLE

Xin Zhou, Jaime D'Agostino, Lei Li, Chad D. Moore, Garold S. Yost and Xinxin Ding
Drug Metabolism and Disposition April 1, 2012, 40 (4) 642-647; DOI: https://doi.org/10.1124/dmd.111.044081

Citation Manager Formats

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

Share
Rapid CommunicationShort Communication

CYP2A5- AND CYP2F2-MEDIATED BIOACTIVATION OF 3-METHYLINDOLE

Xin Zhou, Jaime D'Agostino, Lei Li, Chad D. Moore, Garold S. Yost and Xinxin Ding
Drug Metabolism and Disposition April 1, 2012, 40 (4) 642-647; DOI: https://doi.org/10.1124/dmd.111.044081
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
    • Introduction
    • Materials and Methods
    • Results and Discussion
    • Authorship Contributions
    • Acknowledgment
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Preincubation Effects on Inhibition of OCT1 by CsA
  • Carbamazepine Metabolite and Hypersensitivity Reactions
  • SULT4A1 Preserves Mitochondrial Function
Show more Short Communications

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics