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Mechanistic Computational Model of Steroidogenesis in H295R Cells: Role of Oxysterols and Cell Proliferation to Improve Predictability of Biochemical Response to Endocrine Active Chemical - Metyrapone.
MedLine Citation:
PMID:  21725065     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The human adrenocortical carcinoma cell line H295R is being used as an in vitro steroidogenesis screening assay to assess the impact of endocrine active chemicals (EACs) capable of altering steroid biosynthesis. To enhance the interpretation and quantitative application of measurement data in risk assessments, we are developing a mechanistic computational model of adrenal steroidogenesis in H295R cells to predict the synthesis of steroids from cholesterol (CHOL), and their biochemical response to EACs. We previously developed a deterministic model that describes the biosynthetic pathways for the conversion of CHOL to steroids, and the kinetics for enzyme inhibition by the EAC, metyrapone (MET). In this study, we extended our dynamic model by (1) including a cell proliferation model supported by additional experiments, and (2) adding a pathway for the biosynthesis of oxysterols (OXY), which are endogenous products of CHOL not linked to steroidogenesis. The cell proliferation model predictions closely matched the time-course measurements of the number of viable H295R cells. The extended steroidogenesis model estimates closely correspond to the measured time-course concentrations of CHOL and 14 adrenal steroids both in the cells and medium, and the calculated time-course concentrations of OXY from control and MET-exposed cells. Our study demonstrates the improvement of the extended, more biologically-realistic model to predict CHOL and steroid concentrations in H295R cells and medium, and their dynamic biochemical response to the EAC, MET. This mechanistic modeling capability could help define mechanisms of action for poorly characterized chemicals for predictive risk assessments.
Authors:
Miyuki Breen; Michael S Breen; Natsuko Terasaki; Makoto Yamazaki; Alun L Lloyd; Rory B Conolly
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-7-1
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-7-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA (breen.miyuki@epa.gov).
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