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

o-Hydroxyphenylacetaldehyde Is a Hepatotoxic Metabolite of Coumarin

Stephanie L. Born, Joanna K. Hu and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition February 2000, 28 (2) 218-223;
Stephanie L. Born
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joanna K. Hu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lois D. Lehman-McKeeman
  • 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

o-Hydroxyphenylacetaldehyde (o-HPA), the product of coumarin 3,4-epoxide, was synthesized and its contribution to the hepatotoxic effects of coumarin in the rat was determined. The relative toxicity of coumarin and o-HPA were initially assessed in Chinese hamster ovary K1 (CHO K1) cells, a cell line that does not contain cytochrome P450. In CHO K1 cells,o-HPA-mediated toxicity greatly exceeded that of coumarin. CHO K1 cell viability, determined via the reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), was decreased by 95 and 6% in cultures containingo-HPA and coumarin (4 mM), respectively. Coumarin ando-HPA were then incubated in metabolically competent primary rat hepatocyte cultures. Cell viability was determined via the reduction of MTT, and lactic dehydrogenase (LDH) release was used as a measure of cytotoxicity. Concentration-dependent decreases in cell viability and increased LDH release were observed using 0.2 to 0.8 mMo-HPA and coumarin, with coumarin being consistently less toxic than o-HPA. Cell viability was decreased by 11 and 50% at 0.5 mM coumarin or o-HPA, respectively. Hepatocyte LDH release increased 5-fold after a 6-h exposure to 0.8 mMo-HPA, corresponding to a greater than 90% loss of cell viability in these cultures. In contrast, 0.8 mM coumarin decreased cell viability by 60%, an effect likely due to the conversion of coumarin to coumarin epoxide and o-HPA. Furthermore, 3-hydroxycoumarin (0.8 mM), which is not a product of coumarin epoxidation, had no effect on cell viability or hepatocellular LDH release. These studies demonstrate that metabolically active rat hepatocytes convert coumarin into toxic metabolites, and strongly suggest that o-HPA and coumarin 3,4-epoxide mediate the toxicity of coumarin in rodents in vivo.

Footnotes

  • Send reprint requests to: Dr. Stephanie L. Born, The Procter & Gamble Company, Miami Valley Laboratories, PO Box 538707, Cincinnati, OH 45253-8707. E-mail: born.sl{at}pg.com

  • ↵1 This work was presented in part at the 37th Annual Meeting of The Society of Toxicology, Seattle, WA, March 1998.

  • This work was supported in part by the Research Institute for Fragrance Materials, Hackensack, New Jersey.

  • Abbreviations used are::
    CHO K1
    Chinese hamster ovary
    o-HPA
    o-hydroxyphenylacetaldehyde
    o-HPAA
    o-hydroxyphenylacetic acid
    LDH
    lactic dehydrogenase
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide
    DMSO
    dimethyl sulfoxide
    • Received August 19, 1999.
    • Accepted October 27, 1999.
  • 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: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
  • 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.
o-Hydroxyphenylacetaldehyde Is a Hepatotoxic Metabolite of Coumarin
(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

o-Hydroxyphenylacetaldehyde Is a Hepatotoxic Metabolite of Coumarin

Stephanie L. Born, Joanna K. Hu and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition February 1, 2000, 28 (2) 218-223;

Citation Manager Formats

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

Share
Research ArticleArticle

o-Hydroxyphenylacetaldehyde Is a Hepatotoxic Metabolite of Coumarin

Stephanie L. Born, Joanna K. Hu and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition February 1, 2000, 28 (2) 218-223;
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

  • Human ADME Properties of Abrocitinib
  • MSCs Pharmacokinetics under liver diseases
  • In Vitro P450 Suppression by Peptide Not Observed in Clinic
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