The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

  1. Brecklinghaus, Tim ORCID logo
  2. Albrecht, Wiebke
  3. Kappenberg, Franziska ORCID logo
  4. Duda, Julia Christin ORCID logo
  5. Vartak, Nachiket ORCID logo
  6. Edlund, Karolina ORCID logo
  7. Marchan, Rosemarie ORCID logo
  8. Ghallab, Ahmed ORCID logo
  9. Cadenas, Cristina ORCID logo
  10. Günther, Georgia
  11. Leist, Marcel ORCID logo
  12. Zhang, Mian
  13. Gardner, Iain
  14. Reinders, Joerg ORCID logo
  15. Russel, Frans ORCID logo
  16. Foster, Alison ORCID logo
  17. Williams, Dominic ORCID logo
  18. Damle-Vartak, Dr. Amruta ORCID logo
  19. Grandits, Melanie
  20. Ecker, Gerhard
  21. Kittana, Naim ORCID logo
  22. Rahnenführer, Jörg ORCID logo
  23. Hengstler, Jan ORCID logo

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WeightNameValue
1000 Titel
  • The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds
1000 Autor/in
  1. Brecklinghaus, Tim |
  2. Albrecht, Wiebke |
  3. Kappenberg, Franziska |
  4. Duda, Julia Christin |
  5. Vartak, Nachiket |
  6. Edlund, Karolina |
  7. Marchan, Rosemarie |
  8. Ghallab, Ahmed |
  9. Cadenas, Cristina |
  10. Günther, Georgia |
  11. Leist, Marcel |
  12. Zhang, Mian |
  13. Gardner, Iain |
  14. Reinders, Joerg |
  15. Russel, Frans |
  16. Foster, Alison |
  17. Williams, Dominic |
  18. Damle-Vartak, Dr. Amruta |
  19. Grandits, Melanie |
  20. Ecker, Gerhard |
  21. Kittana, Naim |
  22. Rahnenführer, Jörg |
  23. Hengstler, Jan |
1000 Erscheinungsjahr 2021
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-10-27
1000 Erschienen in
1000 Quellenangabe
  • 351:109728
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.cbi.2021.109728 |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S0009279721003665?via%3Dihub#appsec1 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • An in vitro/in silico method that determines the risk of human drug induced liver injury in relation to oral doses and blood concentrations of drugs was recently introduced. This method utilizes information on the maximal blood concentration (Cmax) for a specific dose of a test compound, which can be estimated using physiologically-based pharmacokinetic modelling, and a cytotoxicity test in cultured human hepatocytes. In the present study, we analyzed if the addition of an assay that measures the inhibition of bile acid export carriers, like BSEP and/or MRP2, to the existing method improves the differentiation of hepatotoxic and non-hepatotoxic compounds. Therefore, an export assay for 5-chloromethylfluorescein diacetate (CMFDA) was established. We tested 36 compounds in a concentration-dependent manner for which the risk of hepatotoxicity for specific oral doses and the capacity to inhibit hepatocyte export carriers are known. Compared to the CTB cytotoxicity test, substantially lower EC10 values were obtained using the CMFDA assay for several known BSEP and/or MRP2 inhibitors. To quantify if the addition of the CMFDA assay to our test system improves the overall separation of hepatotoxic from non-hepatotoxic compounds, the toxicity separation index (TSI) was calculated. We obtained a better TSI using the lower alert concentration from either the CMFDA or the CTB test (TSI: 0.886) compared to considering the CTB test alone (TSI: 0.775). In conclusion, the data show that integration of the CMFDA assay with an in vitro test battery improves the differentiation of hepatotoxic and non-hepatotoxic compounds in a set of compounds that includes bile acid export carrier inhibitors.
1000 Sacherschließung
lokal DILI
lokal cholestasis
lokal transport
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0001-6650-9166|https://frl.publisso.de/adhoc/uri/QWxicmVjaHQsIFdpZWJrZQ==|https://orcid.org/0000-0001-8066-5333|https://orcid.org/0000-0002-3894-0124|https://orcid.org/0000-0002-2966-4631|https://orcid.org/0000-0002-0276-2143|https://orcid.org/0000-0003-4414-1633|https://orcid.org/0000-0003-0695-3403|https://orcid.org/0000-0003-3374-6418|https://frl.publisso.de/adhoc/uri/R8O8bnRoZXIsIEdlb3JnaWEg|https://orcid.org/0000-0002-3778-8693|https://frl.publisso.de/adhoc/uri/WmhhbmcsIE1pYW4=|https://frl.publisso.de/adhoc/uri/R2FyZG5lciwgSWFpbg==|https://orcid.org/0000-0003-1025-7849|https://orcid.org/0000-0002-7959-2314|https://orcid.org/0000-0002-5192-919X|https://orcid.org/0000-0002-0758-3152|https://orcid.org/0000-0001-6091-4937|https://frl.publisso.de/adhoc/uri/R3JhbmRpdHMsIE1lbGFuaWU=|https://frl.publisso.de/adhoc/uri/RWNrZXIsIEdlcmhhcmQ=|https://orcid.org/0000-0003-2758-271X|https://orcid.org/0000-0002-8947-440X|https://orcid.org/0000-0002-1427-5246
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. Horizon 2020 Framework Programme |
  3. Bundesministerium für Bildung und Forschung |
1000 Fördernummer
  1. 427806116
  2. 681002
  3. 031L0119
1000 Förderprogramm
  1. Research Training Group “Biostatistical Methods for High-Dimensional Data in Toxicology” (RTG 2624, Project P1 and P2)
  2. EU-ToxRisk
  3. LivSysTransfer
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm Research Training Group “Biostatistical Methods for High-Dimensional Data in Toxicology” (RTG 2624, Project P1 and P2)
    1000 Fördernummer 427806116
  2. 1000 joinedFunding-child
    1000 Förderer Horizon 2020 Framework Programme |
    1000 Förderprogramm EU-ToxRisk
    1000 Fördernummer 681002
  3. 1000 joinedFunding-child
    1000 Förderer Bundesministerium für Bildung und Forschung |
    1000 Förderprogramm LivSysTransfer
    1000 Fördernummer 031L0119
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6434329.rdf
1000 Erstellt am 2022-07-27T14:59:42.107+0200
1000 Erstellt von 254
1000 beschreibt frl:6434329
1000 Bearbeitet von 317
1000 Zuletzt bearbeitet Wed Aug 31 10:56:14 CEST 2022
1000 Objekt bearb. Wed Aug 31 10:55:39 CEST 2022
1000 Vgl. frl:6434329
1000 Oai Id
  1. oai:frl.publisso.de:frl:6434329 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
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