title: Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells.
abstract: Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.
authors.affiliation: Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Biology Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama 335-8505, Japan; DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kisarazu-shi, Chiba 292-0818, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Terasaki
authors.affiliation: DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kisarazu-shi, Chiba 292-0818, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Masutomi
authors.affiliation: Safety Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kisarazu-shi, Chiba 292-0818, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tsutsui
authors.affiliation: Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okamoto