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

Transcriptomic Hepatotoxicity Signature of Chlorpromazine after Short- and Long-Term Exposure in Primary Human Sandwich Cultures

Céline Parmentier, Germaine L. Truisi, Konrad Moenks, Sven Stanzel, Arno Lukas, Annette Kopp-Schneider, Eliane Alexandre, Philip G. Hewitt, Stefan O. Mueller and Lysiane Richert
Drug Metabolism and Disposition October 2013, 41 (10) 1835-1842; DOI: https://doi.org/10.1124/dmd.113.052415
Céline Parmentier
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Germaine L. Truisi
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Konrad Moenks
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sven Stanzel
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arno Lukas
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Annette Kopp-Schneider
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eliane Alexandre
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip G. Hewitt
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan O. Mueller
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lysiane Richert
KaLy-Cell, Plobsheim, France (C.P., E.A., L.R.); Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany (G.L.T., P.G.H., S.O.M.); Emergentec Biodevelopment GmbH, Vienna, Austria (K.M., A.L.); Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany (S.S., A.K.-S.); Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology, Karlsruhe, Germany (G.L.T., S.O.M.); and Laboratoire de Toxicologie Cellulaire, EA4267 Université de Franche-Comté, Besançon, France (L.R.)
  • 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

Drug-induced liver injury is the most frequent reason for market withdrawal of approved drugs, and is difficult to predict in animal models. Here, we analyzed transcriptomic data derived from short- and long-term cultured primary human hepatocytes (PHH) exposed to the well known human hepatotoxin chlorpromazine (CPZ). Samples were collected from five PHH cultures after short-term (1 and 3 days) and long-term (14 days) repeat daily treatment with 0.1 or 0.2 µM CPZ, corresponding to Cmax. Two PHH cultures were additionally treated with 1 µM CPZ, and the three others with 0.02 µM CPZ. Differences in the total number of gene changes were seen between donors and throughout treatment. Specific transcriptomic hepatotoxicity signatures were created for CPZ and consisted of inflammation/hepatitis, cholestasis, and liver proliferation in all five donors, as well as fibrosis and steatosis, which were observed in four of five donors. Necrosis was present in three of five donors, and an indicative signature of cirrhosis was observed after long-term 14-day repeat treatment, also in three of five donors. The inter-donor variability in the inflammatory response to CPZ treatment was associated with variability in the strength of the response of the transcriptomic hepatotoxicity signatures, suggesting that features of inflammation could be related to the idiosyncratic hepatotoxic effects of CPZ in humans.

Footnotes

    • Received April 19, 2013.
    • Accepted August 2, 2013.
  • This work was supported by EC FP7 (European Commission Seventh Framework Programme) Health Predict-IV “Profiling the toxicity of new drugs: A nonanimal-based approach integrating toxicodynamics and biokinetics” [Grant 202222].

  • C.P. and G.L.T. contributed equally to the work presented in this manuscript.

  • dx.doi.org/10.1124/dmd.113.052415.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 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: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
  • 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.
Transcriptomic Hepatotoxicity Signature of Chlorpromazine after Short- and Long-Term Exposure in Primary Human Sandwich Cultures
(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

Chlorpromazine Toxicity on Human Hepatocyte Sandwich Cultures

Céline Parmentier, Germaine L. Truisi, Konrad Moenks, Sven Stanzel, Arno Lukas, Annette Kopp-Schneider, Eliane Alexandre, Philip G. Hewitt, Stefan O. Mueller and Lysiane Richert
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1835-1842; DOI: https://doi.org/10.1124/dmd.113.052415

Citation Manager Formats

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

Share
Research ArticleArticle

Chlorpromazine Toxicity on Human Hepatocyte Sandwich Cultures

Céline Parmentier, Germaine L. Truisi, Konrad Moenks, Sven Stanzel, Arno Lukas, Annette Kopp-Schneider, Eliane Alexandre, Philip G. Hewitt, Stefan O. Mueller and Lysiane Richert
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1835-1842; DOI: https://doi.org/10.1124/dmd.113.052415
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
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Identification of payload-containing catabolites of ADCs
  • PK Interactions of Licorice with Cytochrome P450s
  • Biotransformation of Trastuzumab and Pertuzumab
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics