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dc.contributor.author
Nudischer, Ramona
dc.contributor.author
Renggli, Kasper
dc.contributor.author
Bertinetti-Lapatki, Cristina
dc.contributor.author
Hoflack, Jean-Christophe
dc.contributor.author
Flint, Nicholas
dc.contributor.author
Sewing, Sabine
dc.contributor.author
Pedersen, Lykke
dc.contributor.author
Schadt, Simone
dc.contributor.author
Higgins, Larry G.
dc.contributor.author
Vardy, Audrey
dc.contributor.author
Lenz, Barbara
dc.contributor.author
Gand, Laurent
dc.contributor.author
Boess, Franziska
dc.contributor.author
Elcombe, Barbara M.
dc.contributor.author
Hierlemann, Andreas
dc.contributor.author
Roth, Adrian B.
dc.date.accessioned
2020-08-24T12:38:39Z
dc.date.available
2020-08-20T10:01:52Z
dc.date.available
2020-08-24T12:38:39Z
dc.date.issued
2020-08
dc.identifier.issn
1096-6080
dc.identifier.issn
1096-0929
dc.identifier.other
10.1093/toxsci/kfaa076
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/432119
dc.description.abstract
Basimglurant (RG7090), a small molecule under development to treat certain forms of depression, demonstrated foci of altered hepatocytes in a long-term rodent-toxicity study. Additional evidence pointed toward the activation of the constitutive androstane receptor (CAR), an established promoter of nongenotoxic and rodent-specific hepatic tumors. This mode of action and the potential human relevance was explored in vivo using rodent and cynomolgus monkey models and in vitro using murine and human liver spheroids. Wild type (WT) and CAR/pregnane X receptor (PXR) knockout mice (CAR/PXR KO) were exposed to RG7090 for 8 consecutive days. Analysis of liver lysates revealed induction of Cyp2b mRNA and enzyme activity, a known activation marker of CAR, in WT but not in CAR/PXR KO animals. A series of proliferative genes were upregulated in WT mice only, and immunohistochemistry data showed increased cell proliferation exclusively in WT mice. In addition, primary mouse liver spheroids were challenged with RG7090 in the presence or absence of modified antisense oligonucleotides inhibiting CAR and/or PXR mRNA, showing a concentration-dependent Cyp2b mRNA induction only if CAR was not repressed. On the contrary, neither human liver spheroids nor cynomolgus monkeys exposed to RG7090 triggered CYP2B mRNA upregulation. Our data suggested RG7090 to be a rodent-specific CAR activator, and that CAR activation and its downstream processes were involved in the foci of altered hepatocytes formation detected in vivo. Furthermore, we demonstrated the potential of a new in vitro approach using liver spheroids and antisense oligonucleotides for CAR knockdown experiments, which could eventually replace in vivo investigations using CAR/PXR KO mice.
en_US
dc.language.iso
en
en_US
dc.publisher
Oxford University Press
en_US
dc.subject
Hepatocyte proliferation
en_US
dc.subject
Nongenotoxic carcinogenesis
en_US
dc.subject
CAR knockout study
en_US
dc.subject
Liver spheroids
en_US
dc.subject
Human risk assessment
en_US
dc.subject
3R
en_US
dc.title
Combining In Vivo and Organotypic In Vitro Approaches to Assess the Human Relevance of Basimglurant (RG7090), a Potential CAR Activator
en_US
dc.type
Journal Article
dc.date.published
2020-05-27
ethz.journal.title
Toxicological Sciences
ethz.journal.volume
176
en_US
ethz.journal.issue
2
en_US
ethz.pages.start
329
en_US
ethz.pages.end
342
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Cary, NC
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03684 - Hierlemann, Andreas / Hierlemann, Andreas
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02060 - Dep. Biosysteme / Dep. of Biosystems Science and Eng.::03684 - Hierlemann, Andreas / Hierlemann, Andreas
ethz.date.deposited
2020-08-20T10:02:03Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2020-08-24T12:38:51Z
ethz.rosetta.lastUpdated
2021-02-15T16:39:58Z
ethz.rosetta.versionExported
true
ethz.COinS
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