Citation:

Breen, M., M. BREEN, N. Terasaki, M. Yamazaki, A. Lloyd, AND R. CONOLLY. The Role of Cholesterol Utilization in a Computational Adrenal Steroidogenesis Model to Improve Predictability of Biochemical Responses to Endocrine Active Chemicals. Presented at North Carolina Society of Toxicology Spring Meeting, Research Triangle Park, NC, February 26, 2009.

Impact/Purpose:

Results show that the model fit improved with the extended model. Model predictions closely correspond to time-course measurements of both cholesterol and steroid concentrations from control and dose-response experiments with MET. Our study indicates that cholesterol is not solely utilized for adrenal steroid synthesis in H295R cells.

Description:

Steroids, which have an important role in a wide range of physiological processes, are synthesized primarily in the gonads and adrenal glands through a series of enzyme-mediated reactions. The activity of steroidogenic enzymes can be altered by a variety of endocrine active chemicals (EAC), some of which are therapeutics and others that are environmental contaminants. We are developing a dynamic mathematical model of the metabolic network of adrenal steroidogenesis to predict the synthesis and secretion of adrenocortical steroids (e.g. mineralocorticoids, glucocorticoids, androgens and estrogens), and the biochemical response to EAC. We previously developed a deterministic model which describes the biosynthetic pathways for the conversion of cholesterol to adrenocortical steroids, and the kinetics for enzyme inhibition by the EAC, metyrapone (MET). In this study, we extended the model by adding a pathway of cholesterol utilization not related to steroidogenesis. Experiments were performed using H295R human adrenocarcinoma cells to measure concentrations of cholesterol and 14 steroids using LC/MS/MS and ELISA methods. Model parameters were estimated using an iterative optimization algorithm.

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