Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Arch Toxicol. 2018 May;92(5):1703-1715. doi: 10.1007/s00204-018-2187-y. Epub 2018 Mar 24.
Obesity is increasing worldwide, and since obesity is associated with dyslipidemia, the consumption of cholesterol-lowering pharmaceuticals has increased. The aim of this study was therefore to study potential endocrine disrupting effects of one of the world's most frequently prescribed drugs, the cholesterol-lowering drug, atorvastatin (ATO) in vitro using the H295R steroidogenesis assay and in vivo using male Sprague-Dawley rats. We analyzed all major steroids in the mammalian steroidogenesis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vitro, ATO significantly decreased all steroids in the H295R steroidogenesis at concentrations close to human plasma C values, with an IC value for testosterone of 0.093 ± 0.033 µM. Additionally, we determined steroid hormone levels in testis, adrenals, brain and plasma from rats after 14 days of exposure to three therapeutically relevant doses of ATO and observed pronounced decreasing steroid levels in particular in testis and adrenals but also in brain and plasma. In testis, all major steroidogenic enzymes were up-regulated, indicating autocrine and/or paracrine compensation for the decrease in steroid production by this tissue. In adrenals, StAR and CYP11A1 gene expression were decreased, whereas little effects were observed in the brain. Furthermore, we analyzed plasma LH and ACTH levels to investigate feedback via the PT and HPA axes. No effects were observed on LH levels, indicating little compensation via the PT axis. In contrast, ACTH levels increased during ATO exposure, indicating that the HPA axis to some extend compensated for the decrease in adrenal steroid production. Overall, ATO exerted pronounced effects on steroid production both in vitro and in vivo at therapeutically relevant doses. This clearly demonstrates the high potency of ATO to affect steroid homeostasis during therapeutic treatment. Further clinical and epidemiological studies should be conducted to investigate the relevance of these observations in patients treated with cholesterol-lowering pharmaceuticals.
肥胖在全球范围内不断增加，由于肥胖与血脂异常有关，因此降低胆固醇的药物的消费也在增加。因此，本研究的目的是使用 H295R 类固醇生成测定法在体外和雄性 Sprague-Dawley 大鼠体内研究世界上最常开处方的药物之一，降胆固醇药物阿托伐他汀（ATO）的潜在内分泌干扰作用。我们使用液相色谱-串联质谱法（LC-MS/MS）分析了哺乳动物类固醇生成中的所有主要类固醇。在体外，ATO 以接近人体血浆 C 值的浓度显着降低了 H295R 类固醇生成中的所有类固醇，其睾酮的 IC 值为 0.093 ± 0.033 µM。此外，我们在暴露于三种治疗相关剂量的 ATO 14 天后测定了大鼠睾丸，肾上腺，大脑和血浆中的类固醇激素水平，并观察到睾丸和肾上腺中类固醇水平明显降低，而在大脑和血浆中也观察到类固醇水平降低。在睾丸中，所有主要的类固醇生成酶均上调，表明该组织类固醇产生减少的自分泌和/或旁分泌补偿。在肾上腺中，StAR 和 CYP11A1 基因表达减少，而在大脑中几乎没有观察到作用。此外，我们还分析了血浆 LH 和 ACTH 水平，以研究通过 PT 和 HPA 轴的反馈。LH 水平没有变化，表明通过 PT 轴的补偿作用很小。相反，在 ATO 暴露期间 ACTH 水平增加，表明 HPA 轴在一定程度上补偿了肾上腺类固醇生成的减少。总体而言，ATO 在治疗相关剂量下在体外和体内均对类固醇生成产生明显影响。这清楚地表明 ATO 在治疗过程中影响类固醇动态平衡的高效力。应进行进一步的临床和流行病学研究，以调查接受降胆固醇药物治疗的患者中这些观察结果的相关性。
