| Title: |
Utility of B-13 Progenitor-Derived Hepatocytes in Hepatotoxicity and Genotoxicity Studies |
| Authors: |
Probert PM; Chung GW; Cockell SJ; Agius L; Mosesso P; White SA; Oakley F; Brown CD; Wright MC |
| Source: |
Toxicological Sciences, 14-11-2013 |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2013 |
| Collection: |
Newcastle University Library ePrints Service |
| Description: |
AR42J B-13 (B-13) cells form hepatocyte-like (B-13/H) cells in response to glucocorticoid treatment. To establish its utility in toxicity and genotoxicity screening, CYP induction; susceptibility to toxins and transporter gene expression were examined. Conversion to B-13/H cells resulted in expression of male-specific CYP2C11 and sensitivity to methapyrilene. B-13/H cells constitutively expressed CYP1A, induced expression in response to an AhR agonist and activated benzo[α]yrene to a DNA damaging species. Functional CYP1A2 was not expressed due to deletions in the CYP1A2 gene. A B-13 cell line stably expressing the human CYP1A2 was therefore engineered (B-13 -TR/h1A2 ) and thederived B-13/H cells expressed metabolically functional CYP1A2. Treatment with the cooked food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine resulted in a dose-dependent increase in DNA damage. B-13/H cells expressed CAR and induced CYP2B1 mRNA levels in response to classical CAR activators. However, translation to functional CYP2B1 protein was low and increased minimally by CAR activator treatment. B-13/H cells expressed high levels of PXR and induced CYP3A1 in response to classical PXR activators. CYP3A genes were inducible, functional and activated aflatoxin B1 to a DNA damaging species. All 23 major hepatic transporters were induced when B-13 cells were converted to B-13/H cells, although in many cases, levels remained below those present in adult rat liver. However, BSEP, Abcb1b, MRP and BCRP transporters were functional in B-13/H cells. These data demonstrate that the B-13 cell generates hepatocyte-like cells with functional drug metabolism and transporter activities which can alone - or in a humanised form - be used to screen for hepatotoxic and genotoxic endpoints in vitro. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://eprints.ncl.ac.uk/196450; https://eprints.ncl.ac.uk/fulltext.aspx?url=196450/C7760474-9C18-4329-BD61-3744CFBEB976.pdf&pub_id=196450 |
| Availability: |
https://eprints.ncl.ac.uk/196450 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.8DEBFDFF |
| Database: |
BASE |