PMID- 27794450
OWN - NLM
STAT- MEDLINE
DCOM- 20170329
LR  - 20181203
IS  - 1879-3177 (Electronic)
IS  - 0887-2333 (Linking)
VI  - 38
DP  - 2017 Feb
TI  - 3D engineered In vitro hepatospheroids for studying drug toxicity and metabolism.
PG  - 8-18
LID - S0887-2333(16)30217-X [pii]
LID - 10.1016/j.tiv.2016.10.009 [doi]
AB  - Drug toxicity is one of the reasons for late stage drug attrition, because of 
      hepatotoxicity. Various in vitro liver models like primary human hepatocytes, 
      immortalized human hepatic cell lines, liver slices and microsomes have been 
      used; but limited by viability, hepatic gene expression and function. The 
      3D-engineered construct of hepatocyte-like-cells (HLCs) differentiated from stem 
      cells, may provide a limitless source of hepatocytes with improved 
      reproducibility. Towards this end, we used hepatospheroids (diameter=50-80mum) 
      differentiated from human-umbilical-cord-mesenchymal stem cells (hUC-MSCs) on 3D 
      scaffold GEVAC (Gelatin-vinyl-acetate-copolymer) as in vitro model for studying 
      drug metabolism/toxicity. Our data demonstrated that 
      hUC-MSCs-derived-hepatospheroids cultured on GEVAC expressed significantly higher 
      drug-metabolizing enzymes (CYPs) both at mRNA and activity level compared to 2D 
      culture, using HR-LC/MS. We further showed that hepatospheroids convert 
      phenacetin (by CYP1A2) and testosterone (by CYP3A4) to their human-specific 
      metabolites acetaminophen and 6beta-hydroxytestosterone with a predictive clearance 
      rate of 0.011ml/h/10(6) cells and 0.021ml/h/10(6) cells respectively, according 
      to first-order kinetics. Hepatotoxicity was confirmed by exposing hepatospheroids 
      to ethanol and acetaminophen; ROS generation, cell viability, cytoskeleton 
      structure, elevation of liver function enzymes, i.e. AST and ALT, was analyzed. 
      To the best of our knowledge, this is the first report to use 
      hUC-MSCs-derived-hepatospheroids on GEVAC as in vitro model for drug 
      metabolism/toxicity study; which can replace the conventional 2D-models used in 
      drug development.
CI  - Copyright A(c) 2016 Elsevier B.V. All rights reserved.
FAU - Chitrangi, Swati
AU  - Chitrangi S
AD  - Department of Biological Sciences, Sunandan Divatia School of Science, SVKM'S 
      NMIMS (Deemed-to-be ) University, V. L Mehta road, Vile Parle (West), Mumbai 
      400056, Maharashtra, India.
FAU - Nair, Prabha
AU  - Nair P
AD  - Division of Tissue Engineering and Regeneration Technologies, Biomedical 
      Technology Wing, Shree Chitra Tirunal Institute for Medical Sciences and 
      Technology, Thiruvananthapuram 695012, Kerala, India.
FAU - Khanna, Aparna
AU  - Khanna A
AD  - Department of Biological Sciences, Sunandan Divatia School of Science, SVKM'S 
      NMIMS (Deemed-to-be ) University, V. L Mehta road, Vile Parle (West), Mumbai 
      400056, Maharashtra, India. Electronic address: aparna.khanna@nmims.edu.
LA  - eng
PT  - Journal Article
DEP - 20161026
PL  - England
TA  - Toxicol In Vitro
JT  - Toxicology in vitro : an international journal published in association with 
      BIBRA
JID - 8712158
RN  - 0 (Pharmaceutical Preparations)
RN  - 0 (Polymers)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Vinyl Compounds)
RN  - 3XMK78S47O (Testosterone)
RN  - 9000-70-8 (Gelatin)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - ER0CTH01H9 (Phenacetin)
RN  - L9MK238N77 (vinyl acetate)
SB  - IM
MH  - *Cell Culture Techniques
MH  - Cells, Cultured
MH  - Cytochrome P-450 Enzyme System/genetics/metabolism
MH  - Drug Evaluation, Preclinical/*methods
MH  - Drug-Related Side Effects and Adverse Reactions
MH  - Gelatin
MH  - Hep G2 Cells
MH  - *Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Mesenchymal Stem Cells/*cytology
MH  - Pharmaceutical Preparations/metabolism
MH  - Phenacetin/pharmacology
MH  - Polymers
MH  - Reactive Oxygen Species/metabolism
MH  - *Spheroids, Cellular/drug effects/metabolism
MH  - Testosterone/pharmacology
MH  - Umbilical Cord/*cytology
MH  - Vinyl Compounds
OTO - NOTNLM
OT  - Drug metabolism
OT  - Hepatospheroid
OT  - Hepatotoxicity testing
OT  - Mesenchymal stem cell
OT  - Pharmacokinetics
OT  - Polymer scaffold
EDAT- 2016/10/31 06:00
MHDA- 2017/03/31 06:00
CRDT- 2016/10/31 06:00
PHST- 2016/06/13 00:00 [received]
PHST- 2016/09/14 00:00 [revised]
PHST- 2016/10/24 00:00 [accepted]
PHST- 2016/10/31 06:00 [pubmed]
PHST- 2017/03/31 06:00 [medline]
PHST- 2016/10/31 06:00 [entrez]
AID - S0887-2333(16)30217-X [pii]
AID - 10.1016/j.tiv.2016.10.009 [doi]
PST - ppublish
SO  - Toxicol In Vitro. 2017 Feb;38:8-18. doi: 10.1016/j.tiv.2016.10.009. Epub 2016 Oct 
      26.