Centre of Biomedicine and Global Health, School of Applied Sciences, Sighthill Campus, Edinburgh Napier University, 9 Sighthill Ct, EH11 4BN Edinburgh, United Kingdom; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano, 49, I-80131 Naples, Italy; Consorzio Interuniversitario INBB, Viale Medaglie d'Oro, 305, I-00136 Rome, Italy.
Centre of Biomedicine and Global Health, School of Applied Sciences, Sighthill Campus, Edinburgh Napier University, 9 Sighthill Ct, EH11 4BN Edinburgh, United Kingdom.
Sci Total Environ. 2024 Mar 20;917:170461. doi: 10.1016/j.scitotenv.2024.170461. Epub 2024 Jan 28.
Five parabens (PBs) i.e., Methylparaben (MP), Ethylparaben (EP), Isopropylparaben (iPrP), Isobutylparaben (iBuP), Benzylparaben (BzP), and their parent compound i.e., para-hydroxy Benzoic Acid (pHBA), were studied both in vitro and in silico. Specifically, we determined their retention on several both protein- (Human Serum Albumin and α-acidic glycoprotein) and (phospho) lipid- (immobilized artificial membrane (IAM)) based biomimetic stationary phases to evaluate their penetration potential through the biomembranes and their possible distribution in the body. The IAM phases were based either on phosphatidylcholine (PC) analogues i.e., PC.MG and PC.DD2 or on sphingomyelin (SPH). We also assessed their viability effect on breast cancer cells (MCF-7) via MTT assay subjecting the cells to five different PB concentrations i.e., 100 μM, 10 μM, 1 μM, 0.1 μM and 0.01 μM. Finally, their pharmacokinetics and toxicity were assessed by the ADMET Predictor™ software. Isopropylparaben was found to be more active than 17β estradiol (E2) employed as positive control, on the screened cell line inducing cell proliferation up to 150 % more of untreated cells. Other analogues showed only a slight/moderate cell proliferation activity, with parabens having longer/branched side chain showing, on average, a higher proliferation rate. Significant linear direct relationships (for PC.DD2 r = 0.89, q = 0.86, for SPH r = 0.89, q = 0.85, for both P value < 0.05) were observed between the difference in proliferative effect between the readout and the control at 0.01 μM concentration and the retention on the IAM phases measured at pH 5.0 for all compounds but pHBA, which is the only analyte of the dataset supporting a carboxylic acid moiety. IAM affinity data measured at pH 7.0 were found to be related to the effective human jejunal permeability as predicted by the software ADMET® Predictor, which is relevant when PBs are added to pharmaceutical and food commodities.
五种对羟基苯甲酸酯（对羟基苯甲酸酯），即甲基对羟基苯甲酸酯（MP）、乙基对羟基苯甲酸酯（EP）、异丙基对羟基苯甲酸酯（iPrP）、异丁基对羟基苯甲酸酯（iBuP）、苄基对羟基苯甲酸酯（BzP）及其母体化合物即对羟基苯甲酸（pHBA），分别在体外和计算机模拟中进行了研究。具体来说，我们确定了它们在几种基于蛋白质（人血清白蛋白和α酸性糖蛋白）和（磷酸）脂质（固定化人工膜（IAM））的仿生固定相上的保留率，以评估它们穿透生物膜的潜力及其在体内的可能分布。IAM 相基于磷脂酰胆碱（PC）类似物，即 PC.MG 和 PC.DD2，或基于鞘磷脂（SPH）。我们还通过 MTT 测定法评估了它们对乳腺癌细胞（MCF-7）的生存能力影响，将细胞暴露于五种不同的 PB 浓度，即 100 μM、10 μM、1 μM、0.1 μM 和 0.01 μM。最后，通过 ADMET Predictor™软件评估了它们的药代动力学和毒性。异丙基对羟基苯甲酸酯的活性比作为阳性对照的 17β 雌二醇（E2）更强，在筛选的细胞系中诱导细胞增殖高达未处理细胞的 150%以上。其他类似物仅显示出轻微/中度的细胞增殖活性，具有较长/支链侧链的对羟基苯甲酸酯显示出更高的增殖率。在所有化合物中，都观察到在 0.01 μM 浓度下与对照相比，读数的增殖效果差异与在 pH 5.0 下测量的 IAM 阶段的保留之间存在显著的线性直接关系（对于 PC.DD2，r=0.89，q=0.86，对于 SPH，r=0.89，q=0.85，对于两者，P 值均<0.05），但 pHBA 除外，pHBA 是数据集中唯一支持羧酸部分的分析物。在 pH 7.0 下测量的 IAM 亲和力数据与软件 ADMET®Predictor 预测的有效人类空肠渗透性相关，当 PBs 添加到药物和食品商品中时，这是相关的。
