PMID- 27344345
OWN - NLM
STAT- MEDLINE
DCOM- 20170306
LR  - 20191210
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Print)
IS  - 0340-5761 (Linking)
VI  - 91
IP  - 3
DP  - 2017 Mar
TI  - Validation of precision-cut liver slices to study drug-induced cholestasis: a 
      transcriptomics approach.
PG  - 1401-1412
LID - 10.1007/s00204-016-1778-8 [doi]
AB  - Hepatotoxicity is one of the major reasons for withdrawal of drugs from the 
      market. Therefore, there is a need to screen new drugs for hepatotoxicity in 
      humans at an earlier stage. The aim of this study was to validate human 
      precision-cut liver slices (PCLS) as an ex vivo model to predict drug-induced 
      cholestasis and identify the possible mechanisms of cholestasis-induced toxicity 
      using gene expression profiles. Five hepatotoxicants, which are known to induce 
      cholestasis (alpha-naphthyl isothiocyanate, chlorpromazine, cyclosporine, ethinyl 
      estradiol and methyl testosterone) were used at concentrations inducing low 
      (<30 %) and medium (30-50 %) toxicity, based on ATP content. Human PCLS were 
      incubated with the drugs in the presence of a non-toxic concentration (60 microM) of 
      a bile acid mixture (portal vein concentration and composition) as model for bile 
      acid-induced cholestasis. Regulated genes include bile acid transporters and 
      cholesterol transporters. Pathway analysis revealed that hepatic cholestasis was 
      among the top ten regulated pathways, and signaling pathways such as farnesoid X 
      receptor- and liver X receptor-mediated responses, which are known to play a role 
      in cholestasis, were significantly affected by all cholestatic compounds. Other 
      significantly affected pathways include unfolded protein response and protein 
      ubiquitination implicating the role of endoplasmic reticulum stress. This study 
      shows that human PCLS incubated in the presence of a physiological bile acid 
      mixture correctly reflect the pathways affected in drug-induced cholestasis in 
      the human liver. In the future, this human PCLS model can be used to identify 
      cholestatic adverse drug reactions of new chemical entities.
FAU - Vatakuti, Suresh
AU  - Vatakuti S
AD  - Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, 
      Groningen, The Netherlands.
FAU - Olinga, Peter
AU  - Olinga P
AD  - Division of Pharmaceutical Technology and Biopharmacy, Groningen Research 
      Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
FAU - Pennings, Jeroen L A
AU  - Pennings JLA
AD  - National Institute for Public Health and the Environment, Bilthoven, The 
      Netherlands.
FAU - Groothuis, Geny M M
AU  - Groothuis GMM
AD  - Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, 
      Groningen, The Netherlands. g.m.m.groothuis@rug.nl.
LA  - eng
PT  - Journal Article
PT  - Validation Study
DEP - 20160625
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 423D2T571U (Ethinyl Estradiol)
RN  - 551-06-4 (1-Naphthylisothiocyanate)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - U42B7VYA4P (Chlorpromazine)
RN  - V9EFU16ZIF (Methyltestosterone)
SB  - IM
MH  - 1-Naphthylisothiocyanate/toxicity
MH  - Aged
MH  - Chlorpromazine/adverse effects
MH  - Cholestasis/*chemically induced/genetics
MH  - Cyclosporine/adverse effects
MH  - Dose-Response Relationship, Drug
MH  - Ethinyl Estradiol/adverse effects
MH  - Female
MH  - Gene Expression Profiling/methods
MH  - Humans
MH  - Liver/*drug effects
MH  - Male
MH  - Methyltestosterone/adverse effects
MH  - Middle Aged
MH  - Signal Transduction/drug effects/genetics
MH  - Transcriptome/drug effects
MH  - Young Adult
PMC - PMC5316400
OTO - NOTNLM
OT  - Cholestasis
OT  - Hepatotoxicity
OT  - Precision-cut liver slices
OT  - Transcriptomics
COIS- The authors declare that they have no conflict of interest.
EDAT- 2016/06/28 06:00
MHDA- 2017/03/07 06:00
PMCR- 2016/06/25
CRDT- 2016/06/27 06:00
PHST- 2015/11/30 00:00 [received]
PHST- 2016/06/20 00:00 [accepted]
PHST- 2016/06/28 06:00 [pubmed]
PHST- 2017/03/07 06:00 [medline]
PHST- 2016/06/27 06:00 [entrez]
PHST- 2016/06/25 00:00 [pmc-release]
AID - 10.1007/s00204-016-1778-8 [pii]
AID - 1778 [pii]
AID - 10.1007/s00204-016-1778-8 [doi]
PST - ppublish
SO  - Arch Toxicol. 2017 Mar;91(3):1401-1412. doi: 10.1007/s00204-016-1778-8. Epub 2016 
      Jun 25.