PMID- 28391356
OWN - NLM
STAT- MEDLINE
DCOM- 20180719
LR  - 20220408
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Print)
IS  - 0340-5761 (Linking)
VI  - 91
IP  - 10
DP  - 2017 Oct
TI  - Rat precision-cut liver slices predict drug-induced cholestatic injury.
PG  - 3403-3413
LID - 10.1007/s00204-017-1960-7 [doi]
AB  - Drug-induced cholestasis (DIC) is one of the leading manifestations of 
      drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not 
      fully known and specific and predictive biomarkers and pre-clinical models are 
      lacking, the occurrence of DIC is often only reported when the drug has been 
      approved for registration. Therefore, appropriate models that predict the 
      cholestatic potential of drug candidates and/or provide insight into the 
      mechanism of DIC are highly needed. We investigated the application of rat 
      precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of 
      cholestasis: hepatocyte viability, intracellular accumulation of total as well as 
      individual bile acids and changes in the expression of genes known to play a role 
      in cholestasis. Rat PCLS exposed to the cholestatic drugs chlorpromazine, 
      cyclosporine A and glibenclamide for 48 h in the presence of a 60 muM 
      physiological bile acid (BA) mix reflected various changes associated with 
      cholestasis, such as decrease in hepatocyte viability, accumulation and changes 
      in the composition of BA and changes in the gene expression of Fxr, Bsep and 
      Ntcp. The toxicity of the drugs was correlated with the accumulation of BA, and 
      especially DCA and CDCA and their conjugates, but to a different extent for 
      different drugs, indicating that BA toxicity is not the only cause for the 
      toxicity of cholestatic drugs. Moreover, our study supports the use of several 
      biomarkers to test drugs for DIC. In conclusion, our results indicate that PCLS 
      may represent a physiological and valuable model to identify cholestatic drugs 
      and provide insight into the mechanisms underlying DIC.
FAU - Starokozhko, Viktoriia
AU  - Starokozhko V
AD  - Division of Pharmacokinetics Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
FAU - Greupink, Rick
AU  - Greupink R
AD  - Department of Pharmacology and Toxicology, Radboud University Medical Center, 
      Nijmegen, The Netherlands.
FAU - van de Broek, Petra
AU  - van de Broek P
AD  - Department of Pharmacology and Toxicology, Radboud University Medical Center, 
      Nijmegen, The Netherlands.
FAU - Soliman, Nashwa
AU  - Soliman N
AD  - Division of Pharmacokinetics Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
FAU - Ghimire, Samiksha
AU  - Ghimire S
AD  - Division of Pharmacokinetics Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
FAU - de Graaf, Inge A M
AU  - de Graaf IAM
AD  - Division of Pharmacokinetics Toxicology and Targeting, Groningen Research 
      Institute for Pharmacy, University of Groningen, Groningen, 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, Groningen, The Netherlands. 
      g.m.m.groothuis@rug.nl.
LA  - eng
PT  - Journal Article
DEP - 20170408
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (Abcb11 protein, rat)
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Organic Anion Transporters, Sodium-Dependent)
RN  - 0 (Symporters)
RN  - 145420-23-1 (sodium-bile acid cotransporter)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
MH  - Animals
MH  - Bile Acids and Salts/metabolism
MH  - Chemical and Drug Induced Liver Injury/*etiology
MH  - Cholestasis/chemically induced
MH  - Gene Expression Regulation/drug effects
MH  - Liver/*drug effects/metabolism/pathology
MH  - Male
MH  - Organ Culture Techniques/*methods
MH  - Organic Anion Transporters, Sodium-Dependent/genetics
MH  - Rats, Wistar
MH  - Symporters/genetics
MH  - Toxicity Tests/*methods
PMC - PMC5608839
OTO - NOTNLM
OT  - Bile acids
OT  - Drug-induced cholestasis
OT  - Drug-induced liver injury
OT  - Precision-cut liver slices
EDAT- 2017/04/10 06:00
MHDA- 2018/07/20 06:00
PMCR- 2017/04/08
CRDT- 2017/04/10 06:00
PHST- 2016/11/09 00:00 [received]
PHST- 2017/03/21 00:00 [accepted]
PHST- 2017/04/10 06:00 [pubmed]
PHST- 2018/07/20 06:00 [medline]
PHST- 2017/04/10 06:00 [entrez]
PHST- 2017/04/08 00:00 [pmc-release]
AID - 10.1007/s00204-017-1960-7 [pii]
AID - 1960 [pii]
AID - 10.1007/s00204-017-1960-7 [doi]
PST - ppublish
SO  - Arch Toxicol. 2017 Oct;91(10):3403-3413. doi: 10.1007/s00204-017-1960-7. Epub 
      2017 Apr 8.