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

Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylation, N-Deacetylation, and β-Lyase-Catalyzed Metabolism

T. Gul Altuntas and Evan D. Kharasch
Drug Metabolism and Disposition February 2002, 30 (2) 148-154; DOI: https://doi.org/10.1124/dmd.30.2.148
T. Gul Altuntas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Evan D. Kharasch
  • 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

Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE; 1) is a fluoroalkene formed by the base-catalyzed degradation of the anesthetic sevoflurane. FDVE is nephrotoxic in rats. In both rats and humans, FDVE undergoes glutathione-dependent conjugation, cleavage to cysteine S-conjugates, and renal β-lyase-catalyzed metabolism to reactive intermediates, which may cause nephrotoxicity. Interindividual variability in renal metabolism of FDVE is unknown. Therefore, this investigation quantified β-lyase-catalyzed bioactivation and N-acetyltransferase-catalyzed inactivation of FDVE cysteine S-conjugates and reactivation of mercapturates by N-deacetylase in cytosol and microsomes from 20 human kidneys. In cytosol,N-acetylation ranged from 0.008 to 0.045 (0.024 ± 0.01) nmol of mercapturate/mg/min and 0.001 to 0.07 (0.024 ± 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteineS-conjugates, respectively. Similar results for microsomal N-acetylation were obtained;N-acetylation ranged from 0.005 to 0.055 (0.025 ± 0.02) nmol of mercapturate/mg/min and 0.001 to 0.06 (0.030 ± 0.02) nmol of mercapturate/mg/min for alkane and alkene cysteineS-conjugates, respectively. β-Lyase-catalyzed metabolism to pyruvate varied from 0.004 to 0.14 (0.051 ± 0.04) nmol/mg/min and from 0.10 to 0.40 (0.26 ± 0.08) nmol/mg/min for alkane and alkene cysteine-S-conjugates, respectively.N-deacetylation of mercapturates ranged from 0.8 to 2.5 (1.25 ± 0.57) nmol of cysteine S-conjugate formed/mg/min and 0.05 to 0.37 (0.17 ± 0.10) nmol of cysteineS-conjugate formed/mg/min for alkane and alkene FDVE mercapturates. Cytosolic cysteine S-conjugates metabolism by renal β-lyase predominated overN-acetylation (ratio of activities was 0.2–6 and 3–146 for the alkane and alkene cysteine S-conjugates).N-deacetylation predominated overN-acetylation (ratio of activities was 20–205 and 2–54 for alkane and alkene S-conjugates). There was considerable (up to 50-fold) interindividual variability in rates of FDVE toxication (β-lyase metabolism andN-deacetylation) and detoxication. This interindividual variability may effect individual susceptibility to the nephrotoxicity of FDVE and other haloalkenes.

Footnotes

  • This study was supported by National Institutes of Health Grant R01 DK53765.

  • Abbreviations used are::
    FDVE
    fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether
    GSH
    glutathione
    LC/MS
    liquid chromatography/mass spectrometry
    GS/MS
    gas chromatography/mass spectrometry
    HKC
    human kidney cytosol
    • Received July 17, 2001.
    • Accepted November 9, 2001.
  • 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: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
  • Table of Contents
  • About the Cover
  • 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.
Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylat…
(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

Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylation, N-Deacetylation, and β-Lyase-Catalyzed Metabolism

T. Gul Altuntas and Evan D. Kharasch
Drug Metabolism and Disposition February 1, 2002, 30 (2) 148-154; DOI: https://doi.org/10.1124/dmd.30.2.148

Citation Manager Formats

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

Share
Research ArticleArticle

Biotransformation of l-CysteineS-Conjugates andN-Acetyl-l-CysteineS-Conjugates of the Sevoflurane Degradation Product Fluoromethyl-2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A) in Human Kidney in Vitro: Interindividual Variability inN-Acetylation, N-Deacetylation, and β-Lyase-Catalyzed Metabolism

T. Gul Altuntas and Evan D. Kharasch
Drug Metabolism and Disposition February 1, 2002, 30 (2) 148-154; DOI: https://doi.org/10.1124/dmd.30.2.148
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Functional Characterization of 29 CYP4F2 Variants
  • Exposure-toxicity relation of apatinib
  • ABC phenomenon potentiates anti-HCC efficacy
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics