Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Toxicol Lett. 2018 Sep 15;294:95-104. doi: 10.1016/j.toxlet.2018.05.022. Epub 2018 May 16.
A critical literature review reveals that knowledge of side effects of pharmaceuticals diclofenac and paracetamol is extremely important because of their widespread use and occurrence in the environment. In order to delineate whether these compounds have endocrine activity and influence on the immune system, we assessed the potential endocrine disrupting and immunomodulatory activities of: diclofenac (DIC), its metabolite 4-hydroxydiclofenac (4-HD) and paracetamol (PAR). Herein, we report on their impact on estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and thyroid hormone receptor (TR). The endocrine disrupting effects were assessed in vitro in MDA-kb2 and GH3.TRE-Luc cell lines and by the XenoScreen YES/YAS assay. Moreover, binding affinity to nuclear receptors (GR and AR) was also measured. Immunomodulatory properties of the compounds were evaluated in lymphoblastoid cell lines. All the tested compounds showed endocrine disrupting and immunomodulatory activities. The results revealed that both DIC and its metabolite 4-HD exhibited significant estrogenic, anti-androgenic (in YAS assay), (anti)-androgenic, (anti)-glucocorticoid and anti-thyroid hormonal activities (in luciferase reporter gene assays). DIC showed direct binding to the GR, while its metabolite 4-HD to the GR and AR. Only metabolite 4-HD showed estrogenic, androgenic (in YAS assay) and thyroid-hormonal activities. PAR had anti-androgenic activity and anti-thyroid hormonal activity. PAR displayed GR agonist activity with competition to its receptor and agonistic activity to AR. All of the compounds significantly modulated pro-inflammatory and immunoregulatory cytokine production in lymphoblastoid cell lines and were thus proven immunomodulatory. The study is useful in determining toxicological effects and contributes to the knowledge of possible side effects of diclofenac, its metabolite and paracetamol.
一项关键的文献综述表明，由于双氯芬酸和扑热息痛的广泛使用及其在环境中的存在，了解它们的副作用极其重要。为了确定这些化合物是否具有内分泌活性和对免疫系统的影响，我们评估了：双氯芬酸（DIC）、其代谢物 4-羟基双氯芬酸（4-HD）和扑热息痛（PAR）的潜在内分泌干扰和免疫调节活性。在此，我们报告了它们对雌激素受体（ER）、雄激素受体（AR）、糖皮质激素受体（GR）和甲状腺激素受体（TR）的影响。内分泌干扰作用通过 MDA-kb2 和 GH3.TRE-Luc 细胞系的体外评估和 XenoScreen YES/YAS 测定进行评估。此外，还测量了它们与核受体（GR 和 AR）的结合亲和力。化合物的免疫调节特性在淋巴母细胞系中进行了评估。所有测试的化合物均表现出内分泌干扰和免疫调节活性。结果表明，DIC 及其代谢物 4-HD 均具有显著的雌激素、抗雄激素（YAS 测定）、（抗）雄激素、（抗）糖皮质激素和抗甲状腺激素活性（荧光素酶报告基因测定）。DIC 显示与 GR 直接结合，而其代谢物 4-HD 与 GR 和 AR 结合。只有代谢物 4-HD 具有雌激素、雄激素（YAS 测定）和甲状腺激素活性。PAR 具有抗雄激素活性和抗甲状腺激素活性。PAR 对 GR 具有激动剂活性，与受体竞争，并对 AR 具有激动剂活性。所有化合物均显著调节淋巴母细胞系中促炎和免疫调节细胞因子的产生，从而具有免疫调节作用。该研究有助于确定毒理学效应，并有助于了解双氯芬酸、其代谢物和扑热息痛可能产生的副作用。
