Inhibition of polyisoprenylated methylated protein methyl esterase by synthetic musks induces cell degeneration
Article first published online: 4 APR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 29, Issue 4, pages 466–477, April 2014
How to Cite
Ayuk-Takem, L., Amissah, F., Aguilar, B. J. and Lamango, N. S. (2014), Inhibition of polyisoprenylated methylated protein methyl esterase by synthetic musks induces cell degeneration. Environ. Toxicol., 29: 466–477. doi: 10.1002/tox.21773
- Issue published online: 6 MAR 2014
- Article first published online: 4 APR 2012
- Manuscript Accepted: 7 FEB 2012
- Manuscript Revised: 2 FEB 2012
- Manuscript Received: 16 JUN 2011
- NIH/NIGMS/SCORE. Grant Number: GM08111-35
- Pharmaceutical Research Center NIH/NCRR. Grant Number: G12 RR0 3020
- polycyclic musks;
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. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 466–477, 2014.