Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells

Figure 5

Estimated mechanism of action of adrenal toxicants by using the mathematical model of adrenal steroidogenesis in NCI-H295R cells. Mechanisms of action of adrenal toxicity compounds were quantitatively estimated from experimental results of differential steroid profiling using the mathematical model of adrenal steroidogenesis in NCI-H295R cells. The drug action was defined as a scaling factor of enzymatic activity in the simulation model. These scaling factors were optimized to fit experimental data by a hybrid optimization method of the RCGA and nonlinear least squares. Estimated drug actions by the exposure of vasculotoxic agents acrylonitrile: AN (a), fumaronitrile: FN (b), salinomycin: SM (c), and thioguanine: TG (d) and the steroidogenic inhibitors aminoglutethimide: AGT (e), o,p′-DDD: DDD (f), spironolactone: SP (g), metyrapone: MP (h), ketoconazole: KC (i), miconazole: MC (j), and daidzein: DZ (k) are shown as a spider radar chart. CYP11A1: P450 side chain cleavage enzyme, CYP17H: 17α-hydroxylase of CYP17, CYP17L: lyase of CYP17, HSD3B2: 3β-hydroxysteroid dehydrogenase, CYP21A2: 21-hydroxylase, CYP11B1: 11β-hydroxylase, CYP11B2: 18-hydroxylase, and HSD17B3: 17β-hydroxysteroid dehydrogenase.

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