Department of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307; Department of Chemistry, College of Arts and Sciences, Florida A&M University, Tallahassee, FL 32307.
Environ Toxicol. 2014 Apr;29(4):466-77. doi: 10.1002/tox.21773. Epub 2012 Apr 4.
Synthetic fragrances are persistent environmental pollutants that tend to bioaccumulate in animal tissues. They are widely used in personal care products and cleaning agents. Worldwide production of Galaxolide and Tonalide are in excess of 4500 tons annually. Because of their widespread production and use, they have been detected in surface waters and fish in the US and Europe. Consumption of contaminated water and fish from such sources leads to bioaccumulation and eventual toxicity. Since fragrances and flavors bear structural similarities to polyisoprenes, it was of interest to determine whether toxicity by Galaxolide and Tonalide may be linked with polyisoprenylated methylated protein methyl esterase (PMPMEase) inhibition. A concentration-dependent study of PMPMEase inhibition by Galaxolide and Tonalide as well as their effects on the degeneration of cultured cells were conducted. Galaxolide and Tonalide inhibited purified porcine liver PMPMEase with Ki values of 11 and 14 μM, respectively. Galaxolide and Tonalide also induced human cancer cell degeneration with EC50 values of 26 and 98 μM (neuroblastoma SH-SY5Y cells) and 58 and 14 μM (lung cancer A549 cells), respectively. The effects on cell viability correlate well with the inhibition of PMPMEase activity in the cultured cells. Molecular docking analysis revealed that the binding interactions are most likely between the fragrance molecules and hydrophobic amino acids in the active site of the enzyme. These results appear to suggest that the reported neurotoxicity of these compounds may be associated with their inhibition of PMPMEase. Exposure to fragrances may pose a significant risk to individuals predisposed to developing degenerative disorders.
合成香料是持久性的环境污染物，往往在动物组织中生物蓄积。它们广泛应用于个人护理产品和清洁剂中。全世界每年生产的加洛赛洛德和托纳莱德超过 4500 吨。由于它们的广泛生产和使用，它们已经在美国和欧洲的地表水和鱼类中被检测到。从这些来源消费受污染的水和鱼类会导致生物蓄积和最终毒性。由于香料和风味与聚异戊二烯具有结构相似性，因此研究加洛赛洛德和托纳莱德的毒性是否与聚异戊二烯甲基化蛋白甲基酯酶（PMPMEase）抑制有关是很有意义的。进行了加洛赛洛德和托纳莱德对 PMPMEase 抑制的浓度依赖性研究以及它们对培养细胞退化的影响。Galaxolide 和 Tonalide 分别以 11 和 14 μM 的 Ki 值抑制纯化的猪肝 PMPMEase。Galaxolide 和 Tonalide 还诱导人癌细胞退化，其 EC50 值分别为 26 和 98 μM（神经母细胞瘤 SH-SY5Y 细胞）和 58 和 14 μM（肺癌 A549 细胞）。细胞活力的影响与培养细胞中 PMPMEase 活性的抑制密切相关。分子对接分析表明，结合相互作用很可能发生在这些香味分子和酶活性部位的疏水性氨基酸之间。这些结果似乎表明，这些化合物的报道的神经毒性可能与其对 PMPMEase 的抑制有关。暴露于香料可能会对易患退行性疾病的个体构成重大风险。
