Kenda Maša, Zore Taja, Sollner Dolenc Marija
University of Ljubljana, Faculty of Pharmacy, SI-1000, Ljubljana, Slovenia.
Chem Biol Interact. 2022 Aug 25;363:110030. doi: 10.1016/j.cbi.2022.110030. Epub 2022 Jun 25.
Some drugs that act on the central nervous system (CNS) are known to affect the endocrine system, although the mechanisms of endocrine toxicity are not well characterized to date. Such CNS drugs include antipsychotics, anticonvulsants, and antidepressants. In the present study, in-vitro firefly luciferase reporter-gene assays using the AR-EcoScreen assay using Chinese hamster ovary (CHO) cell line, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cell lines were used to determine the effects of nine CNS drugs on the androgen receptor, estrogen receptor α, glucocorticoid receptor, and thyroid hormone receptor, respectively. In the AR-EcoScreen assay using CHO cells, anti-androgenic activities were shown for carbamazepine (IC, 167 μM), clonazepam (IC, 26.7 μM), eslicarbazepine acetate (IC, 375 μM), fluoxetine (at 25 μM), lorazepam (IC, 16.4 μM), and sertraline (IC, 8.7 μM). In the hERα-HeLa-9903 cells, estrogen receptor α agonistic activities were shown for fluoxetine, paroxetine, and sertraline (at 10 μM and 25 μM), and in the GH3.TRE-Luc cells, the same three CNS drugs showed antithyroid activities (ICs, 11.6, 11.9, 2.7 μM, respectively). In the hERα-HeLa-9903 cells, estrogen receptor α antagonistic activities were shown for carbamazepine (IC, 114.3 μM), clonazepam (IC, 52.9 μM), and eslicarbazepine acetate (IC, 376.6 μM). When the CNS drugs were tested in the MDA-kb2 cells, none of them showed any activities toward glucocorticoid receptors. Little to no effects were seen toward any of these nuclear receptors for paliperidone and risperidone. The increased signal in the estrogen receptor α agonism assay seen for fluoxetine and paroxetine was confirmed to be mediated through estrogen receptor α. Additionally, we examined the interference of these CNS drugs with the firefly luciferase enzyme. These data elucidate the potential for adverse endocrine effects for some of these CNS drugs, which should therefore contribute to informed choice when prescribing them. However, long-term exposure to therapeutic concentrations of CNS drugs that have activities on the endocrine system should be explored further also in vivo.
已知一些作用于中枢神经系统（CNS）的药物会影响内分泌系统，尽管迄今为止内分泌毒性的机制尚未完全明确。这类中枢神经系统药物包括抗精神病药、抗惊厥药和抗抑郁药。在本研究中，分别使用中国仓鼠卵巢（CHO）细胞系、hERα-HeLa9903、MDA-kb2和GH3.TRE-Luc细胞系，通过AR-EcoScreen检测法进行体外萤火虫荧光素酶报告基因检测，以确定9种中枢神经系统药物对雄激素受体、雌激素受体α、糖皮质激素受体和甲状腺激素受体的影响。在使用CHO细胞的AR-EcoScreen检测中，卡马西平（IC，167 μM）、氯硝西泮（IC，26.7 μM）、醋酸艾司利卡西平（IC，375 μM）、氟西汀（25 μM时）、劳拉西泮（IC，16.4 μM）和舍曲林（IC，8.7 μM）表现出抗雄激素活性。在hERα-HeLa-9903细胞中，氟西汀、帕罗西汀和舍曲林（10 μM和25 μM时）表现出雌激素受体α激动活性，在GH3.TRE-Luc细胞中，同样这三种中枢神经系统药物表现出抗甲状腺活性（IC分别为11.6、11.9、2.7 μM）。在hERα-HeLa-9903细胞中，卡马西平（IC，114.3 μM）、氯硝西泮（IC，52.9 μM）和醋酸艾司利卡西平（IC，376.6 μM）表现出雌激素受体α拮抗活性。当在MDA-kb2细胞中测试这些中枢神经系统药物时，它们均未表现出对糖皮质激素受体的任何活性。帕利哌酮和利培酮对这些核受体几乎没有影响。氟西汀和帕罗西汀在雌激素受体α激动试验中观察到的信号增强被证实是通过雌激素受体α介导的。此外，我们检测了这些中枢神经系统药物对萤火虫荧光素酶的干扰。这些数据阐明了其中一些中枢神经系统药物产生不良内分泌影响的可能性，因此在开处方时应有助于做出明智的选择。然而，对于长期暴露于具有内分泌系统活性的中枢神经系统药物治疗浓度的情况，还应在体内进行进一步研究。
