| Nitromusk and Polycyclic Musk Compounds as Long-Term Inhibitors of Cellular Xenobiotic Defense Systems Mediated by Multidrug Transporters Till Luckenbach and David Epel Hopkins Marine Station of Stanford University, Pacific Grove, California, USA Abstract
Synthetic musk compounds, widely used as fragrances in consumer products, have been detected in human tissue and, surprisingly, in aquatic organisms such as fish and mollusks. Although their persistence and potential to bioaccumulate are of concern, the toxicity and environmental risks of these chemicals are generally regarded as low. Here, however, we show that nitromusks and polycyclic musks inhibit the activity of multidrug efflux transporters responsible for multixenobiotic resistance (MXR) in gills of the marine mussel Mytilus californianus. The IC10 (concentration that inhibits 10%) values for the different classes of musks were in the range of 0.09-0.39 µM, and IC50 values were 0.74-2.56 µM. The immediate consequence of inhibition of efflux transporters is that normally excluded xenobiotics will now be able to enter the cell. Remarkably, the inhibitory effects of a brief 2-hr exposure to musks were only partially reversed after a 24- to 48-hr recovery period in clean seawater. This unexpected consequence of synthetic musks--a long-term loss of efflux transport activity--will result in continued accumulation of normally excluded toxicants even after direct exposure to the musk has ended. These findings also point to the need to determine whether other environmental chemicals have similar long-term effects on these transporters. The results are relevant to human health because they raise the possibility that exposure to common xenobiotics and pharmaceuticals could cause similar long-term inhibition of these transporters and lead to increased exposure to normally excluded toxicants. Key words: chemosensitizers, fragrances, MDR, multidrug resistance, multixenobiotic resistance, MXR, Mytilus californianus, nitromusks, polycyclic musks. Environ Health Perspect 113:17-24 (2005) . doi:10.1289/ehp.7301 available via http://dx.doi.org/ [Online 30 September 2004]
Address correspondence to D. Epel, Hopkins Marine Station of Stanford University, 120 Oceanview Blvd., Pacific Grove, CA 93950 USA. Telephone: (831) 655-6226. Fax: (831) 375-0793. E-mail: depel@stanford.edu We thank C. Chan and S. Sadasivaiah for preliminary studies ; J. Watanabe for help with the statistical analyses ; and I. Corsi, A. Hamdoun, T. Smital, and C. Thaler for discussions and comments on the manuscript. This publication was supported in part by the German Academic Exchange Service (DAAD) , the National Sea Grant College Program of the U.S. Department of Commerce's National Oceanic and Atmospheric Administration under grant R/CZ-182 through the California Sea Grant College Program, and the California State Resources Agency. The views expressed herein do not necessarily reflect the views of any of those organizations. The authors declare they have no competing financial interests. Received 28 May 2004 ; accepted 30 September 2004.
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