Tochitani Tomoaki, Yamashita Akihito, Kouchi Mami, Fujii Yuta, Matsumoto Izumi, Miyawaki Izuru, Yamada Toru, Funabashi Hitoshi
Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Exp Toxicol Pathol. 2016 Feb-Mar;68(2-3):125-31. doi: 10.1016/j.etp.2015.11.004. Epub 2015 Nov 21.
The adrenal gland is the most common toxicological target in the endocrine system, and inhibition of adrenal steroidogenesis by drugs can be fatal in humans. However, methods to evaluate the drug effect are limited. Recently, simultaneous measurement of multiple steroids, including precursors, has become possible. Here, we evaluated the usefulness of this simultaneous measurement for the evaluation of drug effects on adrenal steroidogenesis in vivo. For this purpose, we measured plasma concentrations of adrenal steroids in rats dosed with ketoconazole, a known inhibitor of adrenal steroidogenesis, and examined its relationship with the changes in histopathology and mRNA expression of steroidogenic enzymes in the adrenal gland. Ketoconazole (150mg/kg/day) was orally administered to male rats for 7 days. The adrenal weight was high, and the zona fasciculata/reticularis were hypertrophic with an accumulation of lipid droplets. mRNA expression of CYP11A1, a rate-limiting enzyme in adrenal steroidogenesis, was slightly high in the adrenal gland. Plasma concentration of deoxycorticosterone was markedly high, while there were no significant changes in that of corticosterone, progesterone, or pregnenolone. The changes in the adrenal gland and plasma concentration of steroids were thought to reflect inhibited metabolism of deoxycorticosterone to corticosterone through inhibition of CYP11B1, and compensatory reaction for the inhibition. The compensatory reaction was thought to have masked decrease of corticosterone. These results suggest that simultaneous measurement of multiple steroids can enable sensitive evaluation of drug effects on adrenal steroidogenesis in vivo, while providing insight into the underlying mechanism of the effect.
肾上腺是内分泌系统中最常见的毒理学靶点，药物抑制肾上腺类固醇生成对人类可能是致命的。然而，评估药物作用的方法有限。最近，同时测量包括前体在内的多种类固醇已成为可能。在此，我们评估了这种同时测量在体内评估药物对肾上腺类固醇生成作用的实用性。为此，我们测量了用酮康唑（一种已知的肾上腺类固醇生成抑制剂）给药的大鼠血浆中肾上腺类固醇的浓度，并研究了其与肾上腺组织病理学变化和类固醇生成酶mRNA表达变化的关系。将酮康唑（150mg/kg/天）口服给予雄性大鼠7天。肾上腺重量增加，束状带/网状带肥大，伴有脂滴积聚。肾上腺类固醇生成的限速酶CYP11A1的mRNA表达略有升高。脱氧皮质酮的血浆浓度显著升高，而皮质酮、孕酮或孕烯醇酮的血浆浓度无显著变化。肾上腺和类固醇血浆浓度的变化被认为反映了通过抑制CYP11B1导致脱氧皮质酮向皮质酮代谢的抑制，以及对这种抑制的代偿反应。这种代偿反应被认为掩盖了皮质酮的降低。这些结果表明，同时测量多种类固醇能够在体内灵敏地评估药物对肾上腺类固醇生成的作用，同时深入了解该作用的潜在机制。
