PMID- 26881866
OWN - NLM
STAT- MEDLINE
DCOM- 20170127
LR  - 20170127
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 29
IP  - 3
DP  - 2016 Mar 21
TI  - Classification of Cholestatic and Necrotic Hepatotoxicants Using Transcriptomics 
      on Human Precision-Cut Liver Slices.
PG  - 342-51
LID - 10.1021/acs.chemrestox.5b00491 [doi]
AB  - Human toxicity screening is an important stage in the development of safe drug 
      candidates. Hepatotoxicity is one of the major reasons for the withdrawal of 
      drugs from the market because the liver is the major organ involved in drug 
      metabolism, and it can generate toxic metabolites. There is a need to screen 
      molecules for drug-induced hepatotoxicity in humans at an earlier stage. 
      Transcriptomics is a technique widely used to screen molecules for toxicity and 
      to unravel toxicity mechanisms. To date, the majority of such studies were 
      performed using animals or animal cells, with concomitant difficulty in 
      interpretation due to species differences, or in human hepatoma cell lines or 
      cultured hepatocytes, suffering from the lack of physiological expression of 
      enzymes and transporters and lack of nonparenchymal cells. The aim of this study 
      was to classify known hepatotoxicants on their phenotype of toxicity in humans 
      using gene expression profiles ex vivo in human precision-cut liver slices 
      (PCLS). Hepatotoxicants known to induce either necrosis (n = 5) or cholestasis (n 
      = 5) were used at concentrations inducing low (<30%) and medium (30-50%) 
      cytotoxicity, based on ATP content. Random forest and support vector machine 
      algorithms were used to classify hepatotoxicants using a leave-one-compound-out 
      cross-validation method. Optimized biomarker sets were compared to derive a 
      consensus list of markers. Classification correctly predicted the toxicity 
      phenotype with an accuracy of 70-80%. The classification is slightly better for 
      the low than for the medium cytotoxicity. The consensus list of markers includes 
      endoplasmic reticulum stress genes, such as C2ORF30, DNAJB9, DNAJC12, SRP72, 
      TMED7, and UBA5, and a sodium/bile acid cotransporter (SLC10A7). This study shows 
      that human PCLS are a useful model to predict the phenotype of drug-induced 
      hepatotoxicity. Additional compounds should be included to confirm the consensus 
      list of markers, which could then be used to develop a biomarker PCR-array for 
      hepatotoxicity screening.
FAU - Vatakuti, Suresh
AU  - Vatakuti S
FAU - Pennings, Jeroen L A
AU  - Pennings JL
AD  - National Institute for Public Health and the Environment , Bilthoven, The 
      Netherlands.
FAU - Gore, Emilia
AU  - Gore E
FAU - Olinga, Peter
AU  - Olinga P
FAU - Groothuis, Geny M M
AU  - Groothuis GM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160309
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Benzofurans)
RN  - 0 (Bile Acids and Salts)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - 423D2T571U (Ethinyl Estradiol)
RN  - 66974FR9Q1 (Chloramphenicol)
RN  - 75CL65GTYR (benziodarone)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - SML2Y3J35T (Colchicine)
RN  - U42B7VYA4P (Chlorpromazine)
RN  - V9EFU16ZIF (Methyltestosterone)
SB  - IM
MH  - Acetaminophen/toxicity
MH  - Aged
MH  - Benzofurans/toxicity
MH  - Bile Acids and Salts/toxicity
MH  - Chloramphenicol/toxicity
MH  - Chlorpromazine/toxicity
MH  - Cholestasis/*chemically induced/genetics
MH  - Colchicine/toxicity
MH  - Cyclosporine/toxicity
MH  - Diethylnitrosamine/toxicity
MH  - Drug-Related Side Effects and Adverse Reactions
MH  - Ethinyl Estradiol/toxicity
MH  - Female
MH  - *Gene Expression Profiling
MH  - Hepatocytes/*drug effects/metabolism
MH  - Humans
MH  - Liver/*drug effects/*metabolism
MH  - Male
MH  - Methyltestosterone/toxicity
MH  - Middle Aged
MH  - Necrosis/*chemically induced/genetics
MH  - Phenotype
MH  - *Toxicogenetics
MH  - Young Adult
EDAT- 2016/02/18 06:00
MHDA- 2017/01/28 06:00
CRDT- 2016/02/17 06:00
PHST- 2016/02/17 06:00 [entrez]
PHST- 2016/02/18 06:00 [pubmed]
PHST- 2017/01/28 06:00 [medline]
AID - 10.1021/acs.chemrestox.5b00491 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2016 Mar 21;29(3):342-51. doi: 10.1021/acs.chemrestox.5b00491. 
      Epub 2016 Mar 9.