Computational model of steroidogenesis in human H295R cells to predict biochemical response to endocrine-active chemicals: model development for metyrapone [corrected] [published erratum appears in ENVIRON HEALTH PERSPECT 2011 Jan;119(1):A11].
Background: An in vitro steroidogenesis assay using the human adrenocortical carcinoma cell line H295R is being evaluated as a possible screening assay to detect and assess the impact of endocrineactive chemicals (EACs) capable of altering steroid biosynthesis. Data interpretation and their quantita...
| Publicado en: | Environmental Health Perspectives Vol. 118; no. 2; pp. 265 - 273 |
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| Autores principales: | , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
National Institute of Environmental Health Sciences
Feb2010
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105310389&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 105310389 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00916765 3B5 jtl: Environmental Health Perspectives issn: 00916765 maglogo: N pubinfo: dt: Feb2010 vid: 118 iid: 2 pid: 56539 pub: National Institute of Environmental Health Sciences place: Research Triangle Park, North Carolina artinfo: ui: 105310389 105310389 2010556387 10.1289/ehp.0901107 NLM20123619 PMC2831928 105310389 ppf: 265 ppct: 8 formats: fmt: @attributes: type: P tig: atl: Computational model of steroidogenesis in human H295R cells to predict biochemical response to endocrine-active chemicals: model development for metyrapone [corrected] [published erratum appears in ENVIRON HEALTH PERSPECT 2011 Jan;119(1):A11]. aug: au: Breen MS Breen M Terasaki N Yamazaki M Conolly RB affil: National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA sug: subj: Adrenal Glands Metabolism Environmental Pollutants Adverse Effects Steroids Metabolism Adrenal Glands Drug Effects Cholesterol Metabolism Funding Source Human Models, Statistical Tissue Culture Techniques ab: Background: An in vitro steroidogenesis assay using the human adrenocortical carcinoma cell line H295R is being evaluated as a possible screening assay to detect and assess the impact of endocrineactive chemicals (EACs) capable of altering steroid biosynthesis. Data interpretation and their quantitative use in human and ecological risk assessments can be enhanced with mechanistic computational models to help define mechanisms of action and improve understanding of intracellular concentration-response behavior. Objectives: The goal of this study was to develop a mechanistic computational model of the metabolic network of adrenal steroidogenesis to estimate the synthesis and secretion of adrenal steroids in human H295R cells and their biochemical response to steroidogenesis-disrupting EAC. Methods: We developed a deterministic model that describes the biosynthetic pathways for the conversion of cholesterol to adrenal steroids and the kinetics for enzyme inhibition by metryrapone (MET), a model EAC. Using a nonlinear parameter estimation method, the model was fitted to the measurements from an in vitro steroidogenesis assay using H295R cells. Results: Model-predicted steroid concentrations in cells and culture medium corresponded well to the time-course measurements from control and MET-exposed cells. A sensitivity analysis indicated the parameter uncertainties and identified transport and metabolic processes that most influenced the concentrations of primary adrenal steroids, aldosterone and cortisol. Conclusions: Our study demonstrates the feasibility of using a computational model of steroidogenesis to estimate steroid concentrations in vitro. This capability could be useful to help define mechanisms of action for poorly characterized chemicals and mixtures in support of predictive hazard and risk assessments with EACs. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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