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

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Irene Antolino-Lobo, Jan Meulenbelt, Sandra M. Nijmeijer, Peter Scherpenisse, Martin van den Berg and Majorie B. M. van Duursen
Drug Metabolism and Disposition July 2010, 38 (7) 1105-1112; DOI: https://doi.org/10.1124/dmd.110.032359
Irene Antolino-Lobo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jan Meulenbelt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandra M. Nijmeijer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Scherpenisse
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin van den Berg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Majorie B. M. van Duursen
  • 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

Metabolism plays an important role in the toxic effects caused by 3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the contribution of other cytochrome P450 (P450) and phase II metabolism. In this study, we researched the differential roles of phase I P450 enzymes CYP1A2, CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase (GST) and catechol-O-methyltransferase (COMT) on the toxic potential of MDMA. MDMA acts as inhibitor of its own metabolism with a relative potency of inhibition of CYP2D>CYP3A≫ CYP1A in rat liver microsomes and in human liver [immortalized human liver epithelial cells (THLE)] cells transfected with individual CYP1A2, CYP3A4, or CYP2D6. Cytotoxicity measurements [by 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] in THLE cells showed that the inhibition of phase I enzymes CYP1A2 by α-naphthoflavone and CYP3A4 by troleandomycin does not affect MDMA-induced cytotoxicity. MDMA metabolism by CYP2D6 significantly increased cytotoxicity, which was counteracted by CYP2D6 inhibition by quinidine. Inhibition of COMT by 2′-fluoro-3,4-dihydroxy-5-nitrobenzophenone (Ro-41-0960) and GST by buthionine sulfoximine showed that COMT is mainly involved in detoxification of CYP2D6-formed MDMA metabolites, whereas glutathione (GSH) is mainly involved in detoxification of CYP3A4-formed MDMA metabolites. Liquid chromatography/tandem mass spectrometry analyses of MDMA-metabolites in the THLE cell culture media confirmed formation of the specific MDMA metabolites and corroborated the observed cytotoxicity. Our data suggest that CYP2D6 as well as CYP3A4 play an important role in MDMA bioactivation. In addition, further studies are needed to address the differential roles of CYP3A4 and GSH/GST in MDMA bioactivation and detoxification.

Footnotes

  • This work was supported by the National Institute of Public Health (RIVM), Bilthoven, The Netherlands [Project Number S/660001].

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

    doi:10.1124/dmd.110.032359.

  • ABBREVIATIONS:

    MDMA
    3,4-methylendioxymethamphetamine
    HHMA
    3,4-dihydroxymetamphetamine
    HHA
    3,4-dihydroxyamphetamine
    COMT
    catechol-O-methyltransferase
    HMMA
    4-hydroxy-3-methoxymethamphetamine
    MDA
    3,4-methylendioxyamphetamine
    P450
    cytochrome P450
    THLE
    immortalized human liver epithelial cells
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    GSH
    glutathione
    GST
    glutathione-S-transferase
    HMA
    4-hydroxy-3-methoxyamphetamine
    α-NF
    α-naphtophlavone
    QUI
    quinidine
    TAO
    troleandomycin
    Ro-41-0960
    2′-fluoro-3,4-dihydroxy-5-nitrobenzophenone
    BSO
    buthionine sulfoximine
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    MTR
    methoxyresorufin
    BFC
    7-benzyloxy-4-(trifluoromethyl)coumarin
    AMMC
    3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin
    DMEM/F12
    Dulbecco's modified Eagle medium/Ham's F-12 nutrient mix
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    THLE-Neo
    THLE cells transfected with an empty vector.

  • Received January 20, 2010.
  • Accepted April 13, 2010.
  • Copyright © 2010 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: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
  • 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.
Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity
(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

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Irene Antolino-Lobo, Jan Meulenbelt, Sandra M. Nijmeijer, Peter Scherpenisse, Martin van den Berg and Majorie B. M. van Duursen
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1105-1112; DOI: https://doi.org/10.1124/dmd.110.032359

Citation Manager Formats

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

Share
Research ArticleArticle

Differential Roles of Phase I and Phase II Enzymes in 3,4-Methylendioxymethamphetamine-Induced Cytotoxicity

Irene Antolino-Lobo, Jan Meulenbelt, Sandra M. Nijmeijer, Peter Scherpenisse, Martin van den Berg and Majorie B. M. van Duursen
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1105-1112; DOI: https://doi.org/10.1124/dmd.110.032359
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

  • P450 cell lines for xenobiotic metabolite generation
  • New Dog, Cat, and Pig P450 2J Enzymes
  • Human ADME properties of abrocitinib
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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics