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首页> 外文期刊>The Journal of toxicological sciences >Physiological and drug-induced changes in blood levels of adrenal steroids and their precursors in cynomolgus monkeys: An application of steroid profiling by LC-MS/MS for evaluation of the adrenal toxicity
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Physiological and drug-induced changes in blood levels of adrenal steroids and their precursors in cynomolgus monkeys: An application of steroid profiling by LC-MS/MS for evaluation of the adrenal toxicity

机译：生理和药物诱导的肾上腺类固醇血液水平的变化及其在Cynomolgus猴子中的前体：LC-MS / MS的施用类固醇分析，用于评估肾上腺毒性

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摘要

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.
机译：肾上腺是内分泌系统中最常见的药物毒理学靶标，对人类的抑制抑制肾上腺素甾体系。然而，评估肾上腺毒性的方法是有限的。本研究的目的是验证同时测量多个肾上腺类固醇的血液水平的有用性，包括前体，作为评估肾上腺素猴中肾上腺类甾体系的药物影响的方法。通过这种目的，研究了肾上腺类固醇的生理和药物诱导的血液水平变化，包括皮质醇，醛固酮，雄激素及其前体。首先，对于生理变化，在雄性和雌性鱼腥猴中，检查了血液类固醇水平的盘子系和白天变化。这些动物显示出与人类类似的类固醇水平的昼夜变化，同时在雄性中间的变化相对较小。接下来，使用甲烷酶和甲嘧啶诱导的血液类固醇水平的变化进行检查，通过抑制CYP酶来抑制肾上腺类固醇。与大鼠和人类一致，酮康唑和甲状腺藻酮均增加了脱氧细胞酮和脱氧硅基醇水平，可能是通过CYP11B1抑制的，并且早先观察到升高，并且具有比皮质醇水平的变化更大的动态范围。还观察到反映药物机制的其他类固醇水平的变化。总之，这项研究表明，在鱼糜猴中，同时测量肾上腺类固醇的血液水平，包括前体，可以是敏感地评估对肾上腺甾体制性和研究潜在机制的药物影响的有价值的方法。

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